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

Abstract

Purpose We aimed to compare the efficacy and safety of recombinant human follicle-stimulating hormone (follitropin alfa) and purified urinary human follicle-stimulating hormone (urofollitropin) for ovulation induction in Japanese women with anovulatory infertility;also to verify the noninferiority (in terms of ovulation rate) of follitropin alfa versus urofollitropin. Methods In a Phase III, multicenter, single-blind, parallel-group study, we enrolled 265 Japanese women aged 20-39 years. The patients were menstruating without apparent ovulation or were amenorrheic (with a positive progestin challenge test), and had failed to conceive with anti-estrogen ovulation-induction therapy. The patients underwent a low-dose step-up regimen using follitropin alfa or urofollitropin with a starting dose of 75 IU. The primary endpoint was the proportion of patients who ovulated (mid-luteal serum progesterone C5 ng/mL and/or confirmed clinical pregnancy). Secondary endpoints included the proportion of patients with a dominant follicle (C18 mm) and the duration of stimulation. Results Ovulation occurred in 79.1% and 82.6% of the patients who received follitropin alfa and urofollitropin, respectively, in the full-analysis set (n = 261), and in 79.2% and 82.5% of the per-protocol set (n = 251). The predefined noninferiority criteria for the primary endpoint were achieved. No significant differences were observed in 123Reprod Med Biol (2010) 9:99-106 DOI 10.1007 any secondary endpoint. Treatment-emergent adverse events were reported by a similar proportion of patients in each group (follitropin alfa, 53.5%; urofollitropin, 50.0%). Conclusions No significant difference in the primary efficacy endpoint (rate of ovulation) was observed between follitropin alfa and purified urofollitropin in women with anovulatory infertility who were menstruating or had progestin-positive amenorrhea. The use of treatment holidays in this study prevents comparison of the data with previous trials that utilized consecutive daily doses.

Phase III trial comparing the efficacy and safety of recombinant‐ or urine‐derived human chorionic gonadotropin for ovulation triggering in Japanese women diagnosed with anovulation or oligo‐ovulation and undergoing ovulation induction with follitropin‐alfa

“…The ovulation rate following a single 5000 IU dose of u‐hCG as part of an ovulation induction cycle using r‐hFSH in a low‐dose, step‐up protocol was assumed to be 95%, based on observations from two Japanese trials of r‐hFSH for ovulation induction . An ovulation rate of 95% also was observed in a global phase III trial that investigated a single 250 μg dose of r‐hCG as part of an ovulation induction cycle using r‐hFSH with a similar low‐dose, step‐up protocol…”

“…Assuming that the ovulation rate would be 95% in both arms, 72 evaluable participants (48 treated with r‐hCG and 24 with u‐hCG) were required to demonstrate that the lower limit of the two‐sided 95% CI of the difference in the ovulation rate (r‐hCG minus u‐hCG) was above the non‐inferiority margin of −20%, with at least 90% power. Allowing for a 15% cycle cancelation rate (based on the data from the trials that were used in the previous calculation), a total of 87 participants needed to be enrolled in order that 72 might be evaluable.…”

Pilot study of the optimal protocol of low dose step‐up follicle stimulating hormone therapy for infertile women

“…The phase III study of follitropin alpha was conducted adopting the starting dose of 75 IU with increment dose of 37.5 IU. Monofollicular development was achieved only in 33.3% of the patients, and the rates of hCG cancellation and OHSS were 7.0% and 7.8% . Results of the phase II and III trials suggested that 75 IU was somewhat excess as a starting dose for monofollicular development.…”

“…Monofollicular development was achieved only in 33.3% of the patients, and the rates of hCG cancellation and OHSS were 7.0% and 7.8%. 20 Results of the phase II and III trials suggested that 75 IU was somewhat excess as a starting dose for monofollicular development. Based on these data, optimized starting dose seemed to be located between 37.5 IU and 75 IU, which was a reason why we selected 50 IU and 62.5 IU as starting doses using the recent device with every 12.5 IU steps adjustable.…”

Singleton pregnancy outcomes after assisted and non‐assisted reproductive technology in infertile patients

“…Ovulation induction was performed by daily injections of hMG (hMG-Kowa; Kowa Pharmaceutical Co, Tokyo, Japan) starting on day 3 of the menstrual cycle. Some of the recent patients received recombinant FSH [13]. Oocyte maturation was triggered by injecting 10,000 IU hCG (Mochida Pharmaceutical Co., Osaka, Japan).…”