SJ-0021 (Gonalef®) Versus Purified Pituitary Gonadotropin (Fertinorm-P®) for Ovulation Induction in Japanese Infertile Women
Condition: Infertility; Ovulation Induction
MeSH terms: Pituitary Diseases; Infertility
Study type: Interventional
Phase: Phase 3

Summary: 
      Efficacy and safety studies in the past have suggested that a starting dose of 75
      International Unit (IU) of SJ-0021, and an increase in the dose by 37.5 IU every 7 days, are
      safe for treatment of subjects with ovulatory disorders who are infertile due to hypothalamic
      or pituitary dysfunction and have amenorrhea I or anovulatory cycles (including
      oligomenorrhea and polymenorrhea).

      This was a phase III, multicentre, single-blind, parallel-group comparative study conducted
      to provide confirmatory evidence of non-inferiority of SJ-0021 versus purified gonadotropin,
      a comparator drug, for induction of follicle development and ovulation in infertile Japanese
      women and to provide further information on the safety and tolerability of SJ-0021.
    

Detailed description: 
      Follicle stimulating hormone (FSH) is a heterodimeric glycoprotein wherein an alfa subunit
      and a beta subunit are noncovalently bonded. Follicle stimulating hormone is one of the key
      hormones regulating reproductive functions in both female and male mammals, including humans.
      In females, it stimulates the development of ovarian follicles, which carry oocytes, while in
      males it promotes spermatogenesis. Synthesis and secretion of FSH are stimulated by
      gonadotropin releasing hormone (GnRH), a hypothalamic peptide. Complete or partial
      deficiencies in FSH secretion are common causes of infertility in men and women. In women,
      this state is characterized by absence of ovulation or abnormal ovulation. In men, it leads
      to absence of or abnormally low production of spermatozoa. Administration of FSH, either
      alone or in combination with luteinizing hormone (LH), has been used successfully to treat
      these infertility problems. Until recently, only human menopausal gonadotropin (hMG), a
      mixture of human LH and FSH extracted from the urine of post-menopausal women, and purified
      FSH (u-hFSH), which could be used to reduce the LH content, had been available for treatment
      of infertility. In Japan, hMG and u-hFSH are still used to induce ovulation.

      Purified pituitary gonadotropin, which was used as the comparator drug in this clinical
      trial, is a urinary gonadotropin preparation. However, it is not classified as hMG, but
      rather as a purified pituitary gonadotropin (u-hFSH), and is the preparation most commonly
      used in Japan. Since the LH content of u-hFSH is very low, it can be administered relatively
      safely, if adequate care is taken, to patients with polycystic ovary syndrome (PCOS). SJ-0021
      is a recombinant human FSH (r-hFSH) that is produced using Chinese hamster ovary (CHO) cells
      as the host cells. The generic name for SJ-0021 is follitropin alfa for injection, and it is
      marketed overseas as GONAL-f®. It was approved in Japan in January 2006 as being effective in
      inducing spermatogenesis in cases of male hypogonadotropic hypogonadism (MHH).

      OBJECTIVES

        -  To examine the efficacy of SJ-0021 versus purified pituitary gonadotropin for ovulation
           induction and follicle development in subjects with amenorrhea I or anovulatory cycles,
           and to verify the non-inferiority of SJ-0021 versus the comparator drug

        -  To assess the safety of SJ-0021

      This clinical trial comprised of a pretrial observation period, a treatment period [IMP
      administration period], and a post-treatment assessment period. The clinical trial was
      scheduled in such a way that spontaneous menstruation or withdrawal bleeding induced by
      progesterone administration occurred within 28 days after the completion of baseline tests
      conducted during the pretrial observation period. A visit to the trial site was then
      scheduled for any day between Day 2-5 of the spontaneous menstruation or withdrawal bleeding,
      during which actual registration of the subject for randomization and pre-administration
      tests were performed. After completion of pre-administration tests, 75 IU of either SJ-0021
      or purified pituitary gonadotropin that was allocated to the subject was subcutaneously
      administered on the same day (dosing Day 1 of treatment period), and the same daily dose was
      maintained for the first 7 days of the treatment period. On dosing Day 8, the mean diameter
      of the dominant follicle was measured; if it was < 11 mm, the daily IMP dose was increased by
      37.5 IU and this new daily dose was administered for the next 7 days. If the mean diameter of
      the dominant follicle was ≥ 11 mm but < 18 mm, the same (previous) IMP dose was administered
      for the next 7 days. If the mean diameter of the dominant follicle had already reached 18 mm
      or above, administration of the IMP was terminated, and the subject moved on to the post
      treatment assessment period. Similarly, if the mean diameter of the dominant follicle was <
      11 mm on dosing Day 15 or Day 22, the dose was increased; if it was ≥ 11 mm but < 18 mm,
      administration was continued at the same previous dose, and if it was ≥ 18 mm IMP
      administration was terminated. The maximum dose of IMP that can be administered was 187.5
      IU/day and the maximum dosing period for the IMP was 28 days. In addition to Day 8, Day 15
      and Day 22, ultrasound examination can be conducted once or twice a week during the treatment
      period, based on the status of growth of the dominant follicle (and on every visit once the
      dominant follicle has achieved a maximum diameter of 16 mm).

      Examinations for the first day of the post-treatment assessment period were conducted, as
      appropriate, on the day when the mean diameter of the dominant follicle reached ≥ 18 mm or on
      the day after dosing Day 28 of the IMP. The hCG cancellation criterion (i.e. four or more
      ovarian follicles with a mean diameter ≥ 16 mm) was also verified at the same time. If the
      hCG cancellation criterion was not met, a single dose of 5000 IU of hCG was administered
      intramuscularly, within 24 hours of the last ultrasound examination. Mid-luteal phase tests
      were conducted on Day 6 ± 1 and Day 9 ± 1 of the post-treatment assessment period, and a
      final examination was performed on Day 28-31 of the post-treatment assessment period. If the
      pregnancy test (urine) conducted at this final examination was positive, a further pregnancy
      test (ultrasound examination) was performed on Day 35-42 of the post-treatment assessment
      period.

      On the other hand, if the mean diameter of the dominant follicle remained < 16 mm on the day
      after dosing Day 28 of the IMP, or the hCG cancellation criterion was met, hCG administration
      was withheld, and the examinations for the first day of the post-treatment assessment period
      as well as the final examination on Day 28-31 of the post-treatment assessment period were
      performed accordingly.
    

Intervention name(s): Gonalef® (Follitropin alfa); Purified pituitary gonadotropin (Fertinorm-P®)
Intervention type(s): Drug; Drug
Intervention description(s): Subcutaneous administration of follitropin alfa at a dose of 75 IU/day was started on dosing Day 1 and the same daily dose was maintained for the first 7 days of the treatment period. Dose increment by 37.5 IU was permitted on dosing Day 8, Day 15 and Day 22 if the dosage increase criterion was met.; Subcutaneous administration of purified pituitary gonadotropin at a dose of 75 IU/day was started on dosing Day 1 and the same daily dose was maintained for the first 7 days of the treatment period. Dose increment by 37.5 IU was permitted on dosing Day 8, Day 15 and Day 22 if the dosage increase criterion was met.
Other intervention name(s): Gonalef®; follitropin alfa; recombinant human follicle-stimulating hormone; r-hFSH; SJ-0021; Fertinorm-P®; purified urinary human follicle-stimulatin hormone; urofollitropin; u-hFSH
Intervention MeSH terms: Gonadotropins, Pituitary; Hormones; Follicle Stimulating Hormone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Infertility; Ovulation induction; Gonalef® (Follitropin alfa); Purified pituitary gonadotropin (Fertinorm-P®); gonadotropin; Reproductive technologies, assisted; Polycystic ovary syndrome