Comparative clinical outcome following individualized follitropin delta dosing in Chinese women undergoing ovarian stimulation for in vitro fertilization /intracytoplasmic sperm injection

Abstract

Background: To compare the efficacy and safety of follitropin delta in its individualized fixed-dose regimen with follitropin alfa in a conventional adjustable dosing regimen in Chinese women. METHODS: This was a subgroup analysis of the randomized, multi-center, assessor-blind, non-inferiority trial (GRAPE) including 759 Chinese women (aged 20-40 years) recruited in 16 reproductive medicine clinics in China. Women were randomized in a 1:1 ratio to be treated with either follitropin delta dose based on anti-Müllerian hormone (AMH) and body weight or conventional dosing with follitropin alfa following a gonadotropin-releasing hormone (GnRH) antagonist protocol. The primary outcome was ongoing pregnancy rate assessed 10-11 weeks after embryo transfer in the fresh cycle (non-inferiority margin -10.0%).

Results: 378 in the follitropin delta group and 381 in the follitropin alfa group were randomized and exposed. Non-inferiority was confirmed with respect to ongoing pregnancy with rates of 31.0% vs. 25.7% for follitropin delta compared to follitropin alfa, estimated mean difference of 5.1% (95% confidence interval (CI) -1.3% to 11.5%). The clinical pregnancy rate (35.4% vs. 31.5%, P = 0.239) and live birth rate (31.0% vs. 25.5%, P = 0.101) were comparable between the follitropin delta group and the follitropin alfa group. Overall, the individualized follitropin delta treatment resulted in fewer oocytes retrieved compared to follitropin alfa treatment (10.3 ± 6.2 vs. 12.5 ± 7.5, P < 0.001), which was mainly due to fewer oocytes (10.5 ± 6.4 vs. 13.9 ± 7.8) in women with AMH ≥ 15 pmol/L. Accordingly there was a lower incidence of early ovarian hyper-stimulation syndrome (OHSS) and/or preventive interventions (6.1% vs. 11.0%, P = 0.013). A daily follitropin delta dose of 10.2 µg (95% CI: 9.3-11.2 µg) was estimated to provide the same number of oocytes retrieved as a starting dose of 150 IU/d of follitropin alfa.

Conclusion: Follitropin delta in its individualized fixed-dose regimen showed similar efficacy and improved safety compared with follitropin alfa in a conventional adjustable dosing regimen in Chinese women.

Clinical trial registration number: NCT03296527.

Keywords: Algorithm; Dose equivalence; Follitropin delta; Individualized dosing; Ongoing pregnancy; Ovarian hyperstimulation syndrome.

Fig. 1

Flow chart showing the number of women at each stage of the clinical trial. Note: AMH, anti-Müllerian hormone; GnRH, gonadotropin-releasing hormone; hCG: human chorionic gonadotrophin

Fig. 2

Adjustments of treatment doses according to AMH and body weight. Note: AMH, anti-Müllerian hormone.^aWomen randomized to follitropin delta were administered a fixed daily dose according to patients’ serum AMH concentration at screening and body weight at randomization (AMH < 15 pmol/L: 12 mg; AMH ≥ 15 pmol/L: 0.10–0.19 mg/kg, the maximum daily dose was 12 μg). ^bWomen randomized to follitropin alfa were administered a conventional daily dose of 150 IU (11 μg) for the first 5 days, thereafter the dose was adjusted up or down according to follicular response, the maximum daily dose was 450 IU

Fig. 3

Pregnancy and live birth outcomes. Note: hCG: human chorionic gonadotrophin.^aRates are calculated per treatment group as the percentage of women in the FAS. The retrieved rate was defined as women with at least one oocyte retrieved. ^bThe transfer rate was defined as percentage of women with embryo transfer. ^cβhCG rate was defined as percentage of women with a positive test of serum βhCG 2 weeks after transfer. ^dClinical pregnancy rate was defined as percentage of women with at least one gestational sac 5–6 weeks after transfer. ^eVital pregnancy rate was defined as percentage of women with at least one intrauterine gestational sac with fetal heart after transfer. ^fOngoing pregnancy rate was defined as percentage of women with at least one intrauterine viable fetus 10–11 weeks after transfer. ^gLive birth rate was defined as percentage of women with birth of at least one live-born neonate. ^hLive birth rate at 4 weeks after birth was defined as percentage of women with at least one live neonate 4 weeks after birth

Fig. 4

Analysis of dose equivalence. Note: A Number of oocytes retrieved for follitropin delta and 150 IU/day follitropin alfa in the study (n = 759); B Number of follicles ≥ 12 mm at end of stimulation for follitropin delta and 150 IU/day follitropin alfa in the study (n = 759); C Log of serum oestradiol concentrations at the end of stimulation for follitropin delta and 150 IU/day follitropin alfa in the study (n = 759). Estimated means (circles) with 95% confidence intervals (95% CI) and number of patients for the subgroups based on the dose of follitropin delta corresponding to the patients’ AMH concentrations and body weight. The intersection of the blue and red regression lines indicates the dose of follitropin delta estimated to give the same response as 150 IU of follitropin alfa. The estimate dose equivalence factor and its 95% CI are indicated by the arrow and the solid horizontal black line on the x-axis