Infertility Clinical Trial
Official title:
Parallel-Group Comparative Study of SJ-0021 and Purified Pituitary Gonadotropin in Subjects With Amenorrhea I or Anovulatory Cycles - Phase III Single-Blind Study
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.
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.
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Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment
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