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Corifollitropin alfa or rFSH treatment flexibility options for controlled ovarian stimulation: a post hoc analysis of the Engage trial.

ABSTRACT: We sought to determine the impact of treatment flexibility on clinical outcomes in either a corifollitropin alfa or recombinant follicle-stimulating hormone (rFSH) protocol.Post hoc analysis of a prospective, multicenter, randomized, double-blind, double-dummy non-inferiority clinical trial (Engage). Efficacy outcomes were assessed on patients from the Engage trial who started treatment on menstrual cycle day 2 versus menstrual cycle day 3, patients who received rFSH step-down or fixed-dose rFSH, patients who received rFSH on the day of human chorionic gonadotropin (hCG) compared with those who did not, and patients who received hCG when the criterion was reached versus those with a 1-day delay.The effect of each of the treatment flexibility options on ongoing pregnancy rate was not significant. The estimated difference (95% confidence interval) in ongoing pregnancy rate was -4.3% (-9.4%, 0.8%) for patients who started ovarian stimulation on cycle day 2 versus day 3, 1.8% (-4.1%, 7.6%) for patients who received hCG on the day the hCG criterion was met versus 1 day after, 3.2% (-2.1%, 8.6%) for patients who received rFSH on the day of hCG administration versus those who did not, and -5.8% (-13.0%, 1.4%) for patients who received a reduced versus fixed-dose of rFSH from day 8.Treatment flexibility of ovarian stimulation does not substantially affect the clinical outcome in patients' treatment following initiation of ovarian stimulation with either corifollitropin alfa or with daily rFSH in a gonadotropin-releasing hormone antagonist protocol.Trial was registered under ClinicalTrials.gov identifier NCT00696800.

SUBMITTER: Leader A

PROVIDER: S-EPMC3691650 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Corifollitropin alfa or rFSH treatment flexibility options for controlled ovarian stimulation: a post hoc analysis of the Engage trial.

Leader Arthur A Devroey Paul P Witjes Han H Gordon Keith K

Reproductive biology and endocrinology : RB&E 20130611

<h4>Background</h4>We sought to determine the impact of treatment flexibility on clinical outcomes in either a corifollitropin alfa or recombinant follicle-stimulating hormone (rFSH) protocol.<h4>Methods</h4>Post hoc analysis of a prospective, multicenter, randomized, double-blind, double-dummy non-inferiority clinical trial (Engage). Efficacy outcomes were assessed on patients from the Engage trial who started treatment on menstrual cycle day 2 versus menstrual cycle day 3, patients who receive ...[more]

PMID: 23758821

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Project description:STUDY QUESTION:What is the threshold for the prediction of moderate to severe or severe ovarian hyperstimulation syndrome (OHSS) based on the number of growing follicles ? 11 mm and/or estradiol (E2) levels? SUMMARY ANSWER:The optimal threshold of follicles ?11 mm on the day of hCG to identify those at risk was 19 for both moderate to severe OHSS and for severe OHSS. Estradiol (E2) levels were less prognostic of OHSS than the number of follicles ? 11 mm. WHAT IS KNOWN ALREADY:In comparison to long gonadotropin-releasing hormone (GnRH) agonist protocols, the risk of severe OHSS is reduced by approximately 50% in a GnRH antagonist protocol for ovarian stimulation prior to in vitro fertilisation (IVF), while the two protocols provide equal chances of pregnancy per initiated cycle. Nevertheless, moderate to severe OHSS may still occur in GnRH antagonist protocols if human chorionic gonadotropin (hCG) is administered to trigger final oocyte maturation, especially in high responder patients. Severe OHSS following hCG trigger may occur with an incidence of 1-2% in a relatively young (aged 18 to 36 years) IVF population treated in a GnRH-antagonist protocol. STUDY DESIGN, SIZE, DURATION:From the Engage, Ensure and Trust trials, in total, 2,433 women who received hCG for oocyte maturation and for whom the number of follicles ? 11 mm and the level of E2 on the day of hCG administration were known were included in the analyses. PARTICIPANTS/MATERIALS, SETTING, METHODS:The threshold for OHSS prediction of moderate and severe OHSS was assessed in women treated with corifollitropin alfa or daily recombinant follicle stimulation hormone (rFSH) in a gonadotropin-releasing hormone (GnRH)-antagonist protocol. Receiver operating characteristics curve analyses for moderate to severe OHSS and severe OHSS were performed on the combined dataset and the sensitivity and specificity for the optimal threshold of number of follicles ? 11 mm, E2 levels on the day of (hCG), and a combination of both, were determined. MAIN RESULTS AND THE ROLE OF CHANCE:The optimal threshold of follicles ? 11 mm on the day of hCG to identify those at risk of moderate to severe OHSS was 19 (sensitivity and specificity 62.3% and 75.6%, respectively) and for severe OHSS was also 19 (sensitivity and specificity 74.3% and 75.3%, respectively). The positive and negative predictive values were 6.9% and 98.6%, respectively, for moderate to severe OHSS, and 4.2% and 99.5% for severe OHSS. LIMITATIONS, REASONS FOR CAUTION:This was a retrospective analysis of combined data from three trials following ovarian stimulation with two different gonadotropins. WIDER IMPLICATIONS OF THE FINDINGS:For patients with 19 follicles or more ?11 mm on the day of hCG, measures to prevent the development of OHSS should be considered. Secondary preventive measures include cycle cancellation or coasting, use of a GnRH agonist to trigger final oocyte maturation in place of hCG and a freeze all strategy. TRIAL REGISTRATION:ClinicalTrials.gov NCT00702845 NCT00696800 NCT00696878.

Project description:Utilizing corifollitropin alfa in GnRH antagonist (GnRHant) protocol in conjunction with GnRH agonist trigger/freeze-all strategy (corifollitropin alfa/GnRHant protocol) was reported to have satisfactory outcomes in women with polycystic ovary syndrome (PCOS). Although lessening in gonadotropin injections, GnRHant were still needed. In addition to using corifollitropin alfa, GnRHant was replaced with an oral progestin as in progestin primed ovarian stimulation (PPOS) to further reduce the injection burden in this study. We try to investigate whether this regimen (corifollitropin alfa/PPOS protocol) could effectively reduce GnRHant injections and prevent premature LH surge in PCOS patients undergoing IVF/ICSI cycles. This is a retrospective cohort study recruiting 333 women with PCOS, with body weight between 50 and 70 kg, undergoing first IVF/ICSI cycle between August 2015 and July 2018. We used corifollitropin alfa/GnRHant protocol prior to Jan 2017 (n = 160), then changed to corifollitropin alfa/PPOS protocol (n = 173). All patients received corifollitropin alfa 100 μg on menstruation day 2/3 (S1). Additional rFSH was administered daily from S8. In corifollitropin alfa/GnRHant group, cetrorelix 0.25 mg/day was administered from S5 till the trigger day. In corifollitropin alfa/PPOS group, dydrogesterone 20 mg/day was given from S1 till the trigger day. GnRH agonist was used to trigger maturation of oocyte. All good quality day 5/6 embryos were frozen, and frozen-thawed embryo transfer (FET) was performed on subsequent cycle. A comparison of clinical outcomes was made between the two protocols. The primary endpoint was the incidence of premature LH surge and none of the patients occurred. Dydrogesterone successfully replace GnRHant to block LH surge while an average of 6.8 days of GnRHant injections were needed in the corifollitropin alfa/GnRHant group. No patients suffered from ovarian hyperstimulation syndrome (OHSS). The other clinical outcomes including additional duration/dose of daily gonadotropin administration, number of oocytes retrieved, and fertilization rate were similar between the two groups. The implantation rate, clinical pregnancy rate, and live birth rate in the first FET cycle were also similar between the two groups. In women with PCOS undergoing IVF/ICSI treatment, corifollitropin alfa/PPOS protocol could minimize the injections burden with comparable outcomes to corifollitropin alfa/GnRHant protocol.

Project description:STUDY QUESTION:Is corifollitropin alfa 150 ?g equivalent to follitropin beta 300 IU/day for controlled ovarian hyperstimulation (COS) in older women weighing ?50 kg undergoing IVF and/or ICSI in Vietnam? SUMMARY ANSWER:Corifollitropin alfa 150 ?g was equivalent to follitropin beta 300 IU/day with respect to the number of oocytes retrieved, the ongoing, cumulative and live birth rates and obstetric outcomes. WHAT IS KNOWN ALREADY:Corifollitropin alfa is a recombinant FSH (rFSH) preparation with slow absorption and a long half-life allowing administration of a single dose for COS lasting 7 days. Several randomized, controlled clinical trials have reported that COS with corifollitropin alfa is associated with similar outcomes compared with COS using daily rFSH. However, limited data are available in Asian patients. STUDY DESIGN SIZE DURATION:This randomized controlled trial was conducted at a single large IVF centre in Vietnam from June 2015 to August 2016. A total of 400 patients were included, 200 in each treatment group. The primary outcome measure was the number of oocytes retrieved. Patients were followed for 1 year after randomization. PARTICIPANTS /MATERIALS SETTING METHODS:Participants aged 35-42 years with a body weight ?50 kg who were undergoing an IVF cycle were randomized to undergo COS with a single dose of corifollitropin alfa 150 ?g on Day 2 or 3 of the menstrual cycle, or follitropin beta 300 IU/day for 7 days starting on Day 2 or 3 of the menstrual cycle. All underwent ICSI according to standard institutional protocols. A beta hCG test was performed 17 days after ovum pick-up, and positive tests were confirmed on vaginal and/or abdominal ultrasound at 5-6 weeks after embryo transfer (clinical pregnancy) and at ?10 weeks (ongoing pregnancy). Rates of ovarian hyperstimulation syndrome, and maternal and foetal outcomes after one cycle of ICSI were monitored over 12 months. MAIN RESULTS AND THE ROLE OF CHANCE:Patients in the corifollitropin alfa and follitropin beta groups were well matched at baseline (mean age 37.5 ± 1.9 vs 37.7 ± 2.0 years, mean body weight 53.7 ± 5.4 vs 52.5 ± 4.8 kg). There was no significant difference between the corifollitropin alfa and follitropin beta groups in the number of oocytes retrieved (11.4 ± 5.9 vs 10.8 ± 5.8; P = 0.338). The ongoing pregnancy rate (31.5 vs 32.0%; P = 0.99) and live birth rate (30.5 vs 32.0%; P = 0.83) (both per initiated cycle at 12 months after randomization) were also similar in the two treatment groups. Complication rates were low and similar in the corifollitropin alfa and follitropin beta groups, and there were no significant between-group differences in obstetric outcomes. LIMITATIONS REASONS FOR CAUTION:This study had an open-label design, and therefore, the potential for bias cannot be excluded. The findings are only applicable to patient populations with similar characteristics to those enroled in the study. WIDER IMPLICATIONS OF THE FINDINGS:This study adds to the body of evidence supporting the equivalence of corifollitropin alfa and follitropin beta for COS in a variety of patients undergoing IVF and/or ICSI. The ability to provide COS with corifollitropin alfa has the potential to reduce the burden of treatment for patients. STUDY FUNDING/COMPETING INTERESTS:This study was supported by Merck Sharp and Dohme. The authors state that they have no financial or commercial conflicts of interest. TRIAL REGISTRATION NUMBER:The trial was registered with clinicaltrials.gov (NCT02466204). TRIAL REGISTRATION DATE:2 June 2015. DATE OF FIRST PATIENT’S ENROLMENT:19 June 2015.

Project description:INTRODUCTION: Obtaining an adequate number of high-quality oocytes is a major challenge in controlled ovarian hyperstimulation (COH). To date, a range of hormonal and clinical parameters have been used to optimize COH but none have significant predictive value. This variability could be due to the genetic predispositions of single-nucleotide polymorphisms (SNPs). Here, we assessed the individual and combined impacts of thirteen SNPs that reportedly influence the outcome of in vitro fertilisation (IVF) on the ovarian response to rFSH stimulation for patients undergoing intracytoplasmic sperm injection program (ICSI). RESULTS: Univariate analysis revealed that only FSHR, ESR2 and p53 SNPs influenced the number of mature oocytes. The association was statistically significant for FSHR (p=0.0047) and ESR2 (0.0017) in the overall study population and for FSHR (p=0.0009) and p53 (p=0.0048) in subgroup that was more homogeneous in terms of clinical variables. After Bonferroni correction and a multivariate analysis, only the differences for FSHR and ESR2 polymorphisms were still statistically significant. In a multilocus analysis, only the FSHR and AMH SNP combination significantly influenced oocyte numbers in both population (p<0.01). DISCUSSION: We confirmed the impact of FSHR and ESR2 polymorphisms on the IVF outcome. Furthermore, we showed for the first time that a p53 polymorphism (which is already known to impact embryo implantation) could influence the ovarian response. However, given that this result lost its statistical significance after multivariate analysis, more data are needed to draw firm conclusions. Only the FSHR and AMH polymorphism combination appears to influence mature oocyte numbers but this finding also needs to be confirmed. MATERIALS AND METHODS: A 13 gene polymorphisms: FSHR(Asn680Ser), p53(Arg72Pro), AMH(Ile49Ser), ESR2(+1730G>A), ESR1(-397T>C), BMP15(-9C>G), MTHFR1(677C>T), MTHFR2(1298A>C), HLA-G(-725C>G), VEGF(+405G>C), TNF?(-308A>G), AMHR(-482 A>G), PAI-1 (4 G/5 G), multiplex PCR assay was designed to genotype women undergoing ICSI program. We analyzed the overall study population (n=427) and a subgroup with homogeneous characteristics (n=112).

Dataset Information

Corifollitropin alfa or rFSH treatment flexibility options for controlled ovarian stimulation: a post hoc analysis of the Engage trial.

Publications

Corifollitropin alfa or rFSH treatment flexibility options for controlled ovarian stimulation: a post hoc analysis of the Engage trial.

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