Efficacy, safety, and immunogenicity of a biosimilar recombinant human follicle-stimulating hormone (Folitime®) vs. Gonal-f® in women undergoing ovarian stimulation for IVF: A randomized, multicenter, evaluator-blinded, non-inferiority study.

OBJECTIVE: We compared the efficacy, safety, and immunogenicity of a biosimilar recombinant human follicle-stimulating hormone (Folitime®) with Gonal-f® in women undergoing ovarian stimulation for in-vitro fertilization. METHODS: This randomized (1:1), multicenter, assessor-blinded, non-inferiority, parallel-group, controlled study conducted at four infertility clinics in Argentina included infertile normogonadotropic women with ages below 39 years, with menstrual cycles of 25/35 days and a body mass index of 18-32 kg/m2 undergoing assisted reproductive technology therapy. During a 5-day fixed-dose phase, the women received 225 IU/day of Folitime® (n=49) or Gonal-f® (n=44), followed by a dose-adaptation phase up to a maximum of 450 IU/day. The non-inferiority margin for oocyte retrieval was estimated at -4 oocytes (one-sided test). Immunogenicity was investigated on days 9 and 84, following the start of treatment. RESULTS: The mean number of oocytes retrieved was 12.6 (SD 7.4) in the Folitime® group and 13.4 (SD 6.9) in the Gonal-f® group (per protocol analysis, 95% confidence interval = -3.82; 2.33), within the non-inferiority margin. Pregnancy rate at week 10 was 24.4% among subjects treated with Folitime® and 19.5% for subjects treated with Gonal-f®. One serious adverse drug reaction-late mild ovarian hyper stimulation syndrome and deep venous thrombosis in the left deep jugular vein-occurred in a subject treated with Folitime®. None of the subjects developed antibodies against the study drugs. There were no unexpected safety findings. CONCLUSIONS: Folitime® is non-inferior to Gonal-f®, with no differences in the safety profile and has been approved as a biosimilar in Argentina.

Optimizing the number of embryos to transfer on day 5: two should be the limit.

OBJECTIVE: To define the appropriate number of embryos to be transferred at day 5. METHODS: Retrospective analysis of 784 consecutive fresh day-5 embryo transfers performed between 2007 and 2015, divided in three groups: Group A (N = 219): received the only 2 embryos that reached a transferable stage; Group B (N = 357): received 2 selected embryos among several that reached a transferable stage; Group C (N = 208): received the only 3 developing embryos. Clinical pregnancy, implantation, multiple pregnancy and delivery rates were registered. Kruskal-Wallis and Fisher Exact tests were applied as appropriate. RESULTS: Age and previous attempts were comparable in the 3 groups. Compared with Group A, Groups B and C had a higher oocyte recovery (10.7 ± 5.6 vs. 14.7 ± 8.0 vs. 13.8 ± 6.6), fertilization rate (75.97% vs. 81.60% vs. 83.29%) and percentage of embryos reaching a transferable stage on day 5 (39.98% vs. 63.99% vs. 60.97%), as well as a significantly higher clinical pregnancy (42.92% vs. 61.06% vs. 58.17%) and implantation rates (21.09% vs. 40.98% vs. 36.97%). The multiple pregnancy rate was higher in Groups B and C than in Group A (11.70% vs. 31.19% vs. 37.19%). The high order multiple pregnancy rate (> 2) was significantly increased in group C (1.06% vs. 0.92% vs. 14.05%). CONCLUSIONS: In patients with 3 or more day 5 developing embryos, delivery rates are similar if 2 or 3 embryos are transferred. The transfer of 3 embryos carries an unacceptable increase in the risk of high order multiple pregnancy, with its known consequences. According to our data, we should not exceed the number of 2 day-5 fresh embryos transferred.