Randomized, assessor-blind, antimüllerian hormone–stratified, dose-response trial in Japanese in vitro fertilization/intracytoplasmic sperm injection patients undergoing controlled ovarian stimulation with follitropin delta

Abstract

Objective: To establish the relationship between follitropin delta doses (recombinant follicle-stimulating hormone produced from the human cell line PER.C6) and ovarian response in Japanese women undergoing in vitro fertilization/intracytoplasmic sperm injection treatment and to evaluate the influence of initial antim€ ullerian hormone (AMH) levels. Design: Randomized, controlled, assessor-blind, AMH-stratified (low 5.0-14.9 pmol/L; high 15.0-44.9 pmol/L) dose-response trial. Setting: Reproductive medicine clinics. Patient(s): A total of 158 Japanese women (20-39 years of age). Intervention(s): Controlled ovarian stimulation with 6, 9, or 12 mg/d of follitropin delta or 150 IU/d follitropin beta as a reference arm in a gonadotropin-releasing hormone antagonist cycle. Main Outcome Measure(s): Number of oocytes retrieved. Result(s): Among all women who started stimulation, the mean number (AE standard deviation) of oocytes retrieved in the 6 mg/d, 9 mg/ d, and 12 mg/d follitropin delta groups was 7.0 AE 4.1, 9.1 AE 5.6, and 11.6 AE 5.6, respectively, and a significant dose-relation was established, which also remained significant within each AMH strata. Significant dose-responses also were observed for serum estradiol, inhibin A, and progesterone at end-of-stimulation with follitropin delta. The vital pregnancy rate per started cycle with follitropin delta was 19% for 6 mg/d, 20% for 9 mg/d, and 25% for 12 mg/d. The rate of early moderate/severe ovarian hyperstimulation syndrome with follitropin delta was 8% for 6 mg/d, 8% for 9 mg/d, and 13% for 12 mg/d, with 82% of the cases in the high AMH stratum.

Individualized follitropin delta dosing reduces OHSS risk in Japanese IVF/ICSI patients: a randomized controlled trial

“…In the present trial, conventional dosing was associated with an incidence of 19.8% for OHSS and 14.1% for moderate/severe OHSS. This is consistent with previous clinical trials in Japan reporting OHSS rates of 20-22% (Fujiwara, 2015;Ishihara et al, 2020a). The 50% reduction in occurrence of OHSS (11.2%) and moderate/severe OHSS (7.1%) with the individualised dosing approach is therefore clinically relevant and a major improvement for the patients' safety.…”

“…In line with the RCT conducted outside Japan (Nyboe Andersen and Nelson et al, 2017), the present trial also showed that efficacy in terms of pregnancy and live birth rates was not compromised with individualised dosing. The live birth rates of 23.5% for individualised dosing and 18.6% for conventional dosing in Japanese IVF/ICSI patients are in line with the observations made in previous clinical trials conducted in Japan (Follistim, 2015;Ishihara et al, 2020a) and also with what is reported from clinical practice in Japan (Ishihara et al, 2020b).…”

“…The follitropin delta dosing regimen was identical to that previously investigated in non-Japanese women (Nyboe Andersen and Nelson et al, 2017) with the added establishment of 6 µg as the minimum daily dose to account for the generally lower body weight in the Japanese population. A dose-response trial in Japanese women (Ishihara et al, 2020a) followed by modelling and simulation to confirm the appropriateness of the dosing regimen in Japanese women proceeded the present trial. The follitropin delta dosing algorithm (Supplemental Table 3) was programmed in the electronic case report form, which calculated the dose.…”

“…Reducing each woman's risk of OHSS, while not compromising her potential for a successful outcome, is one of the major clinical challenges in COS. In conventional stimulation protocols with transfer of embryo(s)/blastocyst(s) in the fresh cycle, OHSS has been reported to occur at an incidence of 20% or more in Japanese women (Fujiwara, 2015;Ishihara et al, 2020a). The freeze-all strategy, i.e.…”

Pregnancy and neonatal outcomes in fresh and frozen cycles using blastocysts derived from ovarian stimulation with follitropin delta

“…Comprehensive clinical trials have been performed in in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) patients undergoing ovarian stimulation to document the efficacy and safety of follitropin delta versus CHO-derived recombinant FSH preparations [8][9][10][11][12][13]. The trials have mainly focused on fresh cycles and have provided reassuring information on follitropin delta with respect to the clinical performance of fresh blastocysts leading to pregnancy and live birth as well as the safety of the patients.…”