A multicenter, randomized, phase III study comparing the efficacy and safety of follitropin alpha biosimilar and the original follitropin alpha

Barakhoeva, Zarema; Vovk, Lyudmila; Fetisova, Yulia; Marilova, N. A.; Ovchinnikova, M. M.; Tischenko, Marina; Scherbatyuk, Yulia; Kolotovkina, A. V.; Miskun, A. A.; Kasyanova, G. V.; Teterina, T. A.; Zorina, Irina; Belousova, N. Yu.; Morozova, Ekaterina; Yakovenko, S.A.; Apryshko, V.P.; Sichinava, L.; Shalina, Raisa; Polzikov, M. A.

doi:10.1016/j.ejogrb.2019.07.032

Cited by 19 publications

(9 citation statements)

References 22 publications

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“…As a biosimilar, Ovaleap ® meets the EMA's clinical requirements for recombinant human FSHcontaining medicinal products by demonstrating comparability to the already marketed reference product, Gonal-f ® (6). Other biosimilars for Gonal-f ® have been developed and examined in clinical trials, and have been supported by their similar therapeutic and safety profiles, including their similar OHSS incidence proportions (17)(18)(19). The clinical efficacy of Ovaleap ® has been examined in recently published studies that demonstrated similar ongoing clinical pregnancy or cumulative live birth rates compared to other follitropin alfa and follitropin beta preparations (20,21).…”

Section: Discussionmentioning

confidence: 99%

Safety of Ovaleap® (Follitropin Alfa) in Infertile Women Undergoing Superovulation for Assisted Reproductive Technologies: A Multinational Comparative, Prospective Cohort Study

Kaplan

Levy‐Toledano²,

Davies

et al. 2021

Front. Endocrinol.

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BackgroundOvaleap® (follitropin alfa), a recombinant human follicle stimulating hormone, is a biosimilar medicinal product to Gonal-f® and is used for ovarian stimulation. The main objective of this study was to assess the safety and effectiveness of Ovaleap® compared to Gonal-f® in one treatment cycle in routine clinical practice.MethodsSafety of Ovaleap® Follitropin alfa in Infertile women undergoing superovulation for Assisted reproductive technologies (SOFIA) was a prospective cohort study conducted in six European countries. Eligible patients were infertile women undergoing superovulation for assisted reproductive technology, who were administered Ovaleap® or Gonal-f® for ovarian stimulation and were naïve to follicle stimulating hormone treatment. The recruitment ratio was 1:1. The primary endpoint was incidence proportion of ovarian hyperstimulation syndrome (OHSS) and the secondary endpoint was OHSS severity (Grades I, II, III). The effect of risk factors or potential confounders on the odds ratio for OHSS incidence as well as treatment effect on OHSS incidence was explored using univariate logistic regression. Pregnancy and live birth rates were also assessed.ResultsA total of 408 women who were administered Ovaleap® and 409 women who were administered Gonal-f® were eligible for analysis. The incidence proportion of OHSS was 5.1% (95% CI: 3.4, 7.7) in the Ovaleap® cohort and 3.2% (95% CI: 1.9, 5.4) in the Gonal-f® cohort. This difference in OHSS incidence proportion between the two cohorts was not statistically significant neither before (p = 0.159) nor after univariate adjustment for each potential confounder (p > 0.05). The incidence proportion of OHSS severity grades was similar in the two treatment groups (3.4% versus 2.0% for Grade I, 1.2% versus 1.0% for Grade II, and 0.5% versus 0.2% for Grade III, in the Ovaleap® and Gonal-f® cohorts, respectively), without a significant statistical difference (p = 0.865, for each grade). Among patients who had embryo transfer, clinical pregnancy rates were 33% and 31% and live birth rates were 27% and 26%, in the two cohorts, respectively.ConclusionsFindings from the SOFIA study indicate that the incidence proportions of OHSS and OHSS severity, as well as pregnancy and live birth rates, are similar between Ovaleap® and Gonal-f® treatments and corroborate the safety and effectiveness of Ovaleap® as a biosimilar to Gonal-f®.

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Section: Discussionmentioning

confidence: 99%

Safety of Ovaleap® (Follitropin Alfa) in Infertile Women Undergoing Superovulation for Assisted Reproductive Technologies: A Multinational Comparative, Prospective Cohort Study

Kaplan

Levy‐Toledano²,

Davies

et al. 2021

Front. Endocrinol.

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“…This was a subanalysis of data obtained from a multicentre, randomized, embryologist-blinded, parallel-group, therapeutic equivalence study of follitropin alpha biosimilar (ClinicalTrials.gov Identifier: NCT03088137) (21). The major results of this study argue in favour of both investigated follitropins being therapeutically equivalent; therefore, the clinical data obtained in this study for randomized patients in both compared groups can be combined and considered for further analysis in the current substudy.…”

Section: Methodsmentioning

confidence: 99%

“…The flowchart of study recruitment and follow-up is presented in Figure 1. In 2017-2018, 114 women were enrolled in the parental study of the therapeutic equivalence of follitropin alpha in three IVF centres in Moscow, Russia ("AltraVita" Human Reproduction Clinic, Perinatal Medical Center, and Lapino Clinical Hospital) using the following inclusion criteria: women aged 20-35 with a regular menstrual cycle; tubal and/or male causes of infertility factors; first or second attempt at IVF/ ICSI; 18 ≤ BMI ≤ 30 kg/m 2 ; FSH level <10 IU/l, estradiol level <50 pg/ml and AMH level ≥1.0 ng/ml at cycle days 2-5; 4 ≤ antral follicular count (AFC) ≤ 15; no pathology of the endometrium; and no sexually transmitted infections (21). Three women were excluded due to contradictions to ART (n=2) and a severe male factor (sperm concentration <2 10 6 /ml, n=1), and 1 woman refused.…”

Section: Study Populationmentioning

confidence: 99%

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Association of the Serum Folate and Total Calcium and Magnesium Levels Before Ovarian Stimulation With Outcomes of Fresh In Vitro Fertilization Cycles in Normogonadotropic Women

Polzikov¹,

Блинов

Barakhoeva

et al. 2022

Front. Endocrinol.

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BackgroundWomen of reproductive age are recommended to consume folic acid and other supplements before conception and during pregnancy. We aimed to investigate the association of the serum folate and total magnesium (Mg) and calcium (Ca) levels before ovarian stimulation with the outcomes of assisted reproductive technology (ART) in normogonadotropic women.MethodsWe used a subanalysis of data obtained from a multicentre, randomized prospective study (NCT03088137). A total of 110 normogonadotropic, non-advanced aged, non-obese women with tubal and/or male infertility factors were enrolled for the single fresh ovarian stimulation GnRH antagonist cycle. The main outcome measures were the total oocyte yield, mature oocytes, fertilization rate, biochemical, clinical pregnancy, and live birth. Multivariable generalized linear models adjusted for covariates were used with a Poisson distribution and the log link function for adjusted oocyte counts, and a binomial distribution and the log link function were used for adjusted clinical ART outcomes.ResultsThe medians (interquartile range (IQR)) were as follows: baseline serum folate, 20.55 ng/ml (10.8, 32.9); Mg, 19.4 mg/L (18.7, 20.7); Ca, 94 mg/L (91.2, 96.4); and Ca/Mg ratio, 4.78 (4.55, 5.02). Women with higher serum folate concentrations (Q4≥33.0 ng/ml) had significantly lower total numbers of oocytes retrieved (adjusted mean (95% CI) 9.2 (7.6-11.3) vs 12.9 (10.9-15.4, p-trend=0.006)) and lower odds ratios (ORs) (95% CI) of 0.12 (0.02, 0.79) for clinical pregnancy and 0.10 (0.01, 0.70) for live birth compared with women in the lowest quartile (<10.8 ng/ml), all p-trend<0.001. Women in the highest Ca/Mg ratio quartile (≥5.02) had ORs (95% CI) of 6.58 (1.31, 33.04) for biochemical pregnancy, 4.85 (1.02, 23.08) for clinical pregnancy and 4.07 (0.83, 19.9) for the live birth rate compared with women in the lowest quartile (<4.55), all p-trend<0.001.ConclusionsUsing multivariable models, we suggested that a baseline elevated serum folate level (≥33.0 ng/ml) and a lower Ca/Mg ratio were associated with worse ART outcomes in normogonadotropic women. Our findings might be useful for choosing safe dosages of folate, calcium, magnesium and complex supplementation for both fertile women and women undergoing infertility treatment. Further preconception large-scale studies with known micro- and macronutrient statuses of both parents and serum folate, Ca, Mg, and hormone levels, are needed.

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“…Recently, after the NCT03857230 ( Table 1 ) phase I interventional trial demonstrating the safety of the follitropin α biosimilar Primapur ® , a multicenter, randomized (1:1), embryologist-blinded, parallel-group, comparative phase III study (NCT03088137) was performed ( Table 1 ) [ 68 ]. It enrolled good prognosis women aged 20–35 years with tubal and/or male infertility, who underwent COS using a gonadotropin-releasing hormone antagonist (GnRH-ant) protocol.…”

Section: Clinical Trials Comparing Follitropin α mentioning

confidence: 99%

Human Recombinant FSH and Its Biosimilars: Clinical Efficacy, Safety, and Cost-Effectiveness in Controlled Ovarian Stimulation for In Vitro Fertilization

et al. 2020

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Exogenous human follicle-stimulating hormone (hFSH), either derived from extraction and purification from the urine or obtained by recombinant technology in the form of follitropin α, β and δ (rFSH), has been used for decades in the treatment of infertility. The main applications of FSH treatment in the woman have been, and still are, ovulation induction in oligo-anovulatory subjects, and stimulation of the development of a cohort of follicles in patients undergoing controlled ovarian stimulation (COS) for in vitro fertilization (IVF). In the last years, two biosimilars of follitropin alfa, rFSH compounds structurally and functionally similar to the originator, have been approved and marketed for clinical use in Europe. Moreover, some other rFSH biosimilars are currently under investigation. The objective of this article is to review the available evidences comparing the efficacy, safety, and cost-effectiveness of rFSH follitropin alpha originator with its biosimilars, discussing the clinical trials that allowed biosimilars to get registration and marketing authorization.

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A multicenter, randomized, phase III study comparing the efficacy and safety of follitropin alpha biosimilar and the original follitropin alpha

Cited by 19 publications

References 22 publications

Safety of Ovaleap® (Follitropin Alfa) in Infertile Women Undergoing Superovulation for Assisted Reproductive Technologies: A Multinational Comparative, Prospective Cohort Study

Safety of Ovaleap® (Follitropin Alfa) in Infertile Women Undergoing Superovulation for Assisted Reproductive Technologies: A Multinational Comparative, Prospective Cohort Study

Association of the Serum Folate and Total Calcium and Magnesium Levels Before Ovarian Stimulation With Outcomes of Fresh In Vitro Fertilization Cycles in Normogonadotropic Women

Human Recombinant FSH and Its Biosimilars: Clinical Efficacy, Safety, and Cost-Effectiveness in Controlled Ovarian Stimulation for In Vitro Fertilization

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