SJ-0021 (Gonalef®) Versus Purified Pituitary Gonadotropin (Fertinorm-P®) for Ovulation Induction in Japanese Infertile Women

SJ-0021 (Gonalef®) Versus Purified Pituitary Gonadotropin (Fertinorm-P®) for Ovulation Induction in Japanese Infertile Women

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.

Infertility, Ovulation induction, Gonalef® (Follitropin alfa), Purified pituitary gonadotropin (Fertinorm-P®), gonadotropin, Reproductive technologies, assisted, Polycystic ovary syndrome

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.

Participants were considered to have ovulated if serum progesterone (P4) level was greater than or equal to 5 nanogram (ng)/mL on Day 6±1 or 9±1 during the post-treatment assessment period, or if the participant became clinically pregnant.

On Day 6±1 or 9±1 days during post-treatment assessment period (Day 35-42 of post-treatment period for clinical pregnancy)]

Dosing time length was calculated as number of days from the first administration of the IMP until the mean diameter of the dominant follicle was confirmed to have reached 18 mm.

Total Dose of the Investigational Medicinal Product (IMP) Administered to Participants With Dominant Follicle Achieving 18 mm in Mean Diameter

Total dose of IMP administered was defined as the cumulative dose administered from the start of treatment with IMP until the mean diameter of the dominant follicle reached 18 mm.

hCG cancellation criterion was defined as the presence of 4 or more ovarian follicles with a mean diameter greater than or equal to 16 mm. If the hCG cancellation criterion was met, the administration of hCG was withheld. Otherwise, a single intramuscular dose of hCG 5000 IU (Japanese Pharmacopoeia- JP) was administered within 24 hours of the last ultrasound examination.

Single follicle maturation was defined as the presence of the dominant follicle with a mean diameter of 18 mm or greater without concurrent presence of other follicles of 14 mm or larger in diameter.

Biochemical pregnancy was defined as a positive pregnancy test (urinary beta-hCG test) on Day 28-31 of the post-treatment assessment period

Clinical pregnancy was defined as existence of at least one ultrasonography confirmed gestational sac in the uterus, with or without heartbeat.

Ovulation Rate, Where Ovulation is Defined as a Serum P4 Level Greater Than or Equal to 10 ng/mL or Clinical Pregnancy

For this secondary endpoint, participants were considered to have ovulated if serum P4 level was more than or equal to 10 ng/mL on Day 6±1 or 9±1 during the post-treatment assessment period, or if the participant became clinically pregnant.

Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation

AEs: Any untoward medical occurrence in the form of signs, clinically significant abnormalities in laboratory findings, diseases, symptoms, or worsening of complications. TEAEs: AEs that occur during treatment with the IMP. SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition. Participants who discontinued from the study due to AE were also recorded.

OHSS is a syndrome which can manifest with enlarged ovaries, advanced ascites with increased vascular permeability, pleural fluid accumulation, hemoconcentration, and increased blood clotting.

Inclusion Criteria: Women aged 20 to 39 years (inclusive) who hope to bear children Subjects who failed to achieve ovulation or pregnancy despite 2 cycles or more of anti-estrogen therapies (clomiphene citrate, cyclofenil, etc.) Subjects who exhibited withdrawal bleeding in a progesterone test (Includes spontaneous menstruation in subjects with anovulatory cycles.) Subjects having a body mass index between 17.0 and 28.0 at the time of baseline tests Subjects who voluntarily consented in writing to participate in the clinical trial Exclusion Criteria: Subjects with ovarian tumors Subjects with ovarian enlargement not due to PCOS Subjects with genitourinary hemorrhage of unknown cause Subjects who were or may be pregnant, or who were lactating Subjects with history of allergic reaction or hypersensitivity to gonadotropin Subjects with dysfunction of heart, lungs, kidneys, or cardiovascular systems of Grade 2 or higher (in compliance with the Pharmaceutical and Medical Safety Bureau Notification Yakuan No. 80 [issued 29 June 1992]) Subjects with serum progesterone (P4) level ≥ 5 ng/mL in baseline tests Subjects with malignant tumors Subjects with uterine amenorrhea Subjects with elevated levels of serum gonadotropin due to premature ovarian failure (FSH ≥ 20 mIU/mL) Subjects who were infertile due to known adrenal or thyroid dysfunction Subjects who were diagnosed as having hyperprolactinemia Subjects who had been documented or suspected of having intracranial lesions (e.g., pituitary tumors) Infertile subjects involving gynecological factors other than amenorrhea I or anovulatory cycles, and for whom ovulation induction therapy was found to be contraindicated Subjects who had participated in another clinical study within 6 months prior to start of the IMP administration Subjects who had been administered SJ-0021 in the past Subjects whose participation in this clinical trial was otherwise deemed inappropriate by the investigator or sub-investigator

Taketani Y, Kelly E, Yoshimura Y, Hoshiai H, Irahara M, Mizunuma H, Saito H, Andoh K, Yanaihara T. Recombinant follicle-stimulating hormone (follitropin alfa) versus purified urinary follicle-stimulating hormone in a low-dose step-up regimen to induce ovulation in Japanese women with anti-estrogen-ineffective oligo- or anovulatory infertility: results of a single-blind Phase III study. Reprod Med Biol. 2010 Feb 23;9(2):99-106. doi: 10.1007/s12522-010-0046-5. eCollection 2010 Jun.