Randomized, active-controlled, comparative phase 3 efficacy and safety equivalence trial of Ovaleap® (recombinant human follicle-stimulating hormone) in infertile women using assisted reproduction technology (ART)

Abstract

BackgroundPharmacokinetic studies with XM17 (Ovaleap®), a recombinant human follicle-stimulating hormone (r-hFSH, follitropin alfa), have demonstrated good safety and tolerability in healthy women whose endogenous FSH levels were down-regulated with a long agonist protocol. In these studies, Ovaleap® pharmacokinetics were dose-proportional and bioequivalent to the reference follitropin alfa product (Gonal-f®). The objective of the present study is to determine whether Ovaleap® is equivalent to Gonal-f® with respect to the number of oocytes retrieved in infertile but ovulatory women undergoing assisted reproductive technology (ART) therapy.MethodsThis multinational, multicenter, randomized (1:1), active-controlled, assessor-blind, comparative study included infertile normally gonadotrophic women 18 to 37 years old with a body mass index of 18 to 29 kg/m2 and regular menstrual cycles of 21 to 35 days undergoing ART therapy. During a 5-day fixed-dose phase, women received 150 IU/day of Ovaleap® (n = 153) or Gonal-f® (n = 146), followed by an up to 15-day dose-adaptation phase during which doses could be adjusted every 3 to 5 days, up to a maximum of 450 IU/day. Ovaleap® was to be deemed equivalent to Gonal-f® if the two-sided 0.95 confidence interval (CI) for the difference in the number of oocytes retrieved fell within the equivalence range of ±3 oocytes.ResultsSimilar numbers of oocytes were retrieved in the 2 treatment groups. The mean ± SD number of oocytes retrieved was 12.2 ± 6.7 in the Ovaleap® group and 12.1 ± 6.7 in the Gonal-f® group (intent-to-treat [ITT] population). Regression analysis estimated a mean difference of 0.03 oocytes between the treatment groups (95 % CI: −0.76-0.82), which was well within the prespecified equivalence range of ±3 oocytes. Ovaleap® and Gonal-f® showed favorable and comparable safety profiles, with no unexpected safety findings.ConclusionsOvaleap® has shown the same efficacy and safety as Gonal-f® for stimulation of follicular development in infertile women (up to 37 years of age) who are undergoing ART therapy.Trial RegistrationEudraCT: 2009-017674-20. Current controlled trials: ISRCTN74772901. Date of trial registration: 19 March 2010.

No Association between TNF-α -308G/A Polymorphism and Idiopathic Recurrent Miscarriage: A Systematic Review with Meta-Analysis and Trial Sequential Analysis

“…Sensitivity analysis also demonstrated that the overall results were reliable and robust, with no single influential study. All in all, the overall analyses found no significant associations in all five genetic models, which is quite opposite to the results of two recent meta-analyses in 2012 and 2016 [49, 50], whereas consistent with the meta-analysis in 2009 [48] and two reviews about the effect of polymorphisms of TNF-α[54, 55]. …”

“…Therefore, polymorphisms in this region may be associated with IRM risk. And a bunch of studies have been performed to evaluate the association between TNF-α promoter polymorphisms and IRM risk [26–50]. …”

“…Among all the genetic variants in this region, TNF-α -308G/A (rs1800629) is most studied [28–50]. However, the results of these studies are inconsistent and often conflicting.…”

“…However, the results of these studies are inconsistent and often conflicting. Although one meta-analysis of 7 studies in 2009 [48], another one of 12 studies in 2012 [49], and the third one of 10 studies in 2016 [50] have been conducted, their conclusions were conflicting and unreliable due to the inclusion of studies deviating significantly from Hardy-Weinberg equilibrium (HWE) [39, 40], and studies without sufficient data to calculate HWE [44–47]. Meanwhile, a missing study [32] in the previous meta-analyses and a couple of new studies with different results [38, 41, 42] were found by us during the investigation.…”

Usability engineering study in the European Union of a redesigned follitropin alfa pen injector for infertility treatment

“…Several of the injectable drugs used in the treatment of infertility, including follitropin alfa (recombinant human follicle-stimulating hormone), are available in prefilled pen injectors [3][4][5][6]. These pen injectors are designed to make self-injection easier, more discrete, and more accurate, compared with the use of either a prefilled syringe or a syringe and drug vial [3].…”