Individualized follitropin delta dosing reduces OHSS risk in Japanese IVF/ICSI patients: a randomized controlled trial.

RESEARCH QUESTION: This study aimed to establish the efficacy and safety of ovarian stimulation with a follitropin delta individualized fixed-dose regimen based on serum anti-Müllerian hormone (AMH) concentration and body weight versus conventional follitropin beta dosing in Japanese women. DESIGN: This randomized, controlled, assessor-blind, multicentre, non-inferiority trial was conducted in 347 Japanese IVF/intracytoplasmic sperm injection patients. They were randomized to individualized follitropin delta (AMH <15 pmol/l: 12 µg/day; AMH ≥15 pmol/l: 0.10-0.19 µg/kg/day; minimum 6 µg/day; maximum 12 µg/day) or conventional follitropin beta (150 IU/day for the first 5 days, with potential subsequent dose adjustments). The primary end-point was the number of oocytes retrieved with a pre-specified non-inferiority margin (-3.0 oocytes). RESULTS: The primary trial objective was met, as non-inferiority was established for number of oocytes retrieved for individualized follitropin delta dosing compared with conventional follitropin beta dosing (9.3 versus 10.5; lower boundary of 95% confidence interval -2.3). The occurrence of ovarian hyperstimulation syndrome (OHSS) was reduced to approximately half with individualized compared with conventional dosing, with an incidence of 11.2% versus 19.8% (P = 0.021) for OHSS of any grade and 7.1% versus 14.1% (P = 0.027) for moderate/severe OHSS. The live birth rate per started cycle was 23.5% for individualized dosing and 18.6% for conventional dosing. CONCLUSIONS: Dosing with individualized follitropin delta in Japanese women is non-inferior to conventional dosing with follitropin beta for number of oocytes retrieved. The individualized approach shows a favourable benefit-risk profile, providing a statistically significant and clinically relevant reduction in the incidence of OHSS, without compromising live birth rates.

Effectiveness and safety of follitropin alfa (Ovaleap®) for ovarian stimulation using a GnRH antagonist protocol in real-world clinical practice: a multicenter, prospective, open, non-interventional assisted reproductive technology study.

BACKGROUND: The use of recombinant human follicle-stimulating hormone (r-hFSH) in ovarian stimulation protocols for infertility treatment in assisted reproductive technology (ART) clinical practice is well established. More recent advancements include the availability of biosimilar r-hFSH products, which expand the choices available to healthcare practitioners and patients. Better understanding of how such a product contributes to routine clinical practice is valuable to help prescribers make informed treatment choices. The objective of this study was to examine the effectiveness and safety of ovarian stimulation (OS) with follitropin alfa (Ovaleap®) for routine IVF or intracytoplasmic sperm injection treatment in gonadotropin-releasing hormone (GnRH) antagonist cycles in real-world ART clinical practice. METHODS: This non-interventional, multicenter, prospective study was initiated in 34 specialized reproductive medicine centers in Germany. Eligible women were 18-40 years old with a body mass index < 30 kg/m2, menstrual cycle 24-35 days and anti-Müllerian hormone ≥1 ng/mL, who were undergoing a first OS cycle exclusively with Ovaleap® during routine ART using a GnRH antagonist protocol. Primary effectiveness outcomes were number of retrieved oocytes after OS and clinical pregnancy rate (CPR). Secondary outcomes included fertilization rate, number of transferred embryos, live birth delivery rate, safety, and user satisfaction with the Ovaleap® pen. RESULT(S): Of 507 women screened, 463 received at least 1 dose of Ovaleap® and 439 had Visit 2 data (per protocol population; PPP). The mean(±SD) number of retrieved oocytes was 11.8 ± 7.2 (PPP). The CPR among women with documented embryo transfer was 41.3% (158/383), resulting in a live birth delivery rate of 31.6% (138/437) among PPP patients with available follow-up information. Overall, 8.6% (40/463) of women reported ≥1 adverse drug reaction. Ovarian hyperstimulation syndrome occurred in 23 (5.0%) patients, rated mild in 14 (3.0%), moderate in 8 (1.7%), and severe in 1 (0.2%). Patients reported high user satisfaction and high convenience with use of the Ovaleap® pen. CONCLUSION: The effectiveness and safety of OS with Ovaleap® in a GnRH antagonist protocol were extended to real-world ART clinical practice for the first time. TRIAL REGISTRATION: Registered on 22 June 2016 (retrospectively registered) at ClinicalTrials.gov (NCT02809989).

Follitropin delta in repeated ovarian stimulation for IVF: a controlled, assessor-blind Phase 3 safety trial.

RESEARCH QUESTION: To evaluate the immunogenicity of follitropin delta in repeated ovarian stimulation. DESIGN: Controlled, assessor-blind trial in IVF/intracytoplasmic sperm injection patients undergoing repeated cycles of ovarian stimulation (cycles 2 and 3), following initial stimulation with follitropin delta or follitropin alfa (cycle 1) in a preceding randomized trial. In cycles 2 and 3, 513 and 188 women, respectively, were treated as randomized in cycle 1, with dosing based on ovarian response in the previous cycle. RESULTS: The incidence of treatment-induced anti-FSH antibodies with follitropin delta was 0.8% and 1.1% in cycles 2 and 3, respectively, which was similar to the incidence in cycle 1 (1.1%). No antibodies were of neutralizing capacity. Women with pre-existing anti-FSH antibodies were safely treated with follitropin delta without boosting an immune response. Treatment with follitropin delta and follitropin alfa gave similar outcomes for mean number of oocytes retrieved (9.2 versus 8.6 [cycle 2]; 8.3 versus 8.9 [cycle 3]), ongoing pregnancy (27.8% versus 25.7%; 27.4% versus 28.0%) and live birth rates (27.4% versus 25.3%; 26.3% versus 26.9%). The presence of anti-FSH antibodies did not affect the ovarian response. CONCLUSIONS: The trial demonstrated the low immunogenicity potential of follitropin delta in repeated ovarian stimulation, and confirmed the appropriateness of the follitropin delta dosing regimen in repeated cycles, with documented efficacy and safety.

Efficacy and safety of follitropin alfa/lutropin alfa in ART: a randomized controlled trial in poor ovarian responders.

STUDY QUESTION: How does the efficacy and safety of a fixed-ratio combination of recombinant human FSH plus recombinant human LH (follitropin alfa plus lutropin alfa; r-hFSH/r-hLH) compare with that of r-hFSH monotherapy for controlled ovarian stimulation (COS) in patients with poor ovarian response (POR)? SUMMARY ANSWER: The primary and secondary efficacy endpoints were comparable between treatment groups and the safety profile of both treatment regimens was favourable. WHAT IS KNOWN ALREADY: Although meta-analyses of clinical trials have suggested some beneficial effect on reproductive outcomes with r-hLH supplementation in patients with POR, the definitions of POR were heterogeneous and limit the comparability across studies. STUDY DESIGN, SIZE, DURATION: Phase III, single-blind, active-comparator, randomized, parallel-group clinical trial. Patients were followed for a single ART cycle. A total of 939 women were randomized (1:1) to receive either r-hFSH/r-hLH or r-hFSH. Randomization, stratified by study site and participant age, was conducted via an interactive voice response system. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women classified as having POR, based on criteria incorporating the ESHRE Bologna criteria, were down-regulated with a long GnRH agonist protocol and following successful down-regulation were randomized (1:1) to COS with r-hFSH/r-hLH or r-hFSH alone. The primary efficacy endpoint was the number of oocytes retrieved following COS. Safety endpoints included the incidence of adverse events, including ovarian hyperstimulation syndrome (OHSS). Post hoc analyses investigated safety outcomes and correlations between live birth and baseline characteristics (age and number of oocytes retrieved in previous ART treatment cycles or serum anti-Müllerian hormone (AMH)). The significance of the treatment effect was tested by generalized linear models (Poisson regression for counts and logistic regression for binary endpoints) adjusting for age and country. MAIN RESULTS AND THE ROLE OF CHANCE: Of 949 subjects achieving down-regulation, 939 were randomized to r-hFSH/r-hLH (n = 477) or r-hFSH (n = 462) and received treatment. Efficacy assessment: In the intention-to-treat (ITT) population, the mean (SD) number of oocytes retrieved (primary endpoint) was 3.3 (2.71) in the r-hFSH/r-hLH group compared with 3.6 (2.82) in the r-hFSH group (between-group difference not statistically significant). The observed difference between treatment groups (r-hFSH/r-hLH and r-hFSH, respectively) for efficacy outcomes decreased over the course of pregnancy (biochemical pregnancy rate: 17.3% versus 23.9%; clinical pregnancy rate: 14.1% versus 16.8%; ongoing pregnancy rate: 11.0% versus 12.4%; and live birth rate: 10.6% versus 11.7%). An interaction (identified post hoc) between baseline characteristics related to POR and treatment effect was noted for live birth, with r-hFSH/r-hLH associated with a higher live birth rate for patients with moderate or severe POR, whereas r-hFSH was associated with a higher live birth rate for those with mild POR. A post hoc logistic regression analysis indicated that the incidence of total pregnancy outcome failure was lower in the r-hFSH/r-hLH group (6.7%) compared with the r-hFSH group (12.4%) with an odds ratio of 0.52 (95% CI 0.33, 0.82; P = 0.005). Safety assessment: The overall proportion of patients with treatment-emergent adverse events (TEAEs) occurring during or after r-hFSH/r-hLH or r-hFSH use (stimulation or post-stimulation phase) was 19.9% and 26.8%, respectively. There was no consistent pattern of TEAEs associated with either treatment. LIMITATIONS, REASONS FOR CAUTION: Despite using inclusion criteria for POR incorporating the ESHRE Bologna criteria, further investigation is needed to determine the impact of the heterogeneity of POR in the Bologna patient population. The observed correlation between baseline clinical characteristics related to POR and live birth rate, as well as the observed differences between groups regarding total pregnancy outcome failure were from post hoc analyses, and the study was not powered for these endpoints. In addition, the attrition rate for pregnancy outcomes in this trial may not reflect general medical practice. Furthermore, as the patient population was predominantly White these results might not be applicable to other ethnicities. WIDER IMPLICATIONS OF THE FINDINGS: In the population of women with POR investigated in this study, although the number of oocytes retrieved was similar following stimulation with either a fixed-ratio combination of r-hFSH/r-hLH or r-hFSH monotherapy, post hoc analyses showed that there was a lower rate of total pregnancy outcome failure in patients receiving r-hFSH/r-hLH, in addition to a higher live birth rate in patients with moderate and severe POR. These findings are clinically relevant and require additional investigation. The benefit:risk balance of treatment with either r-hFSH/r-hLH or r-hFSH remains positive. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Merck KGaA, Darmstadt, Germany. P.H. has received honoraria for lectures and unrestricted research grants from Ferring, Merck KGaA and MSD. D.R. is a former employee of EMD Serono, a business of Merck KGaA, Darmstadt, Germany. J.S., J.H. and W.C. are employees of EMD Serono Research and Development Institute, a business of Merck KGaA, Darmstadt, Germany. T.D.'H. and S.L. are employees of Merck KGaA, Darmstadt, Germany. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT02047227; EudraCT Number: 2013-003817-16. TRIAL REGISTRATION DATE: ClinicalTrials.gov: 24 January 2014; EudraCT: 19 December 2013. DATE OF FIRST PATIENT'S ENROLMENT: 30 January 2014.

High FSH dosing is associated with reduced live birth rate in fresh but not subsequent frozen embryo transfers.

STUDY QUESTION: Do live birth rates (LBRs) differ between fresh embryo transfer (fresh ET) cycles and their subsequent paired frozen ET (FET) cycles, when comparing cycles based on the total FSH dose used during the fresh cycle? SUMMARY ANSWER: When compared to the paired frozen embryo transfer cycles, the LBR in the fresh cycle of the highest total FSH dose group (>2500 IU) was reduced by 38%. WHAT IS KNOWN ALREADY: There may be a negative association with high gonadotropin doses and LBR after fresh ET. It is unknown whether a similar effect is seen in FET cycles, which are done with increasing frequency. STUDY DESIGN, SIZE, DURATION: In this retrospective observational paired study, we studied IVF cycles between 10 January 2005 and 19 September 2015, for all patients who underwent a fresh, autologous IVF cycle that resulted in at least one fresh ET and at least one FET. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study included 862 women, treated in our academic medical centre, who underwent 935 fresh ET and 1274 FET cycles. Cycles were allocated into three groups based on the total gonadotropin dose they received during their fresh IVF cycle: Group 1 (≤1800 IU FSH), Group 2 (1801-2500 IU), Group 3 (>2500 IU). The primary outcome was LBR after fresh ET and its subsequent paired FET(s), as well as LBR among fresh ETs and FETs as independent samples, based on the total FSH dose used. Implantation rates obtained from fresh and FET cycles were also compared. MAIN RESULTS AND THE ROLE OF CHANCE: The unadjusted fresh LBR was similar between Groups 1 and 2 (46.0% [95% CI: 40.4-51.6] versus 43.8% [38.3-49.4], respectively) but significantly lower in Group 3 (34.4% [29.5-39.8]). The unadjusted frozen transfer LBR was similar among all groups (51.4% [46.7-56.1] versus 46.3% [41.3-51.4] versus 47.5% [42.5-52.4], respectively). When logistic regression analysis with generalized estimating equations was used to control for confounders, the adjusted LBR was found to be similar between the groups both for fresh (odds ratio [OR] = 0.97 [95% CI: 0.61-1.56] Group 2 versus Group 1, OR = 0.69 [0.39-1.21] Group 3 versus Group 1) and FET cycles (OR = 0.87 [0.58-1.31] Group 2 versus Group 1, OR = 0.95 [0.58-1.55] Group 3 versus Group 1). However, for Group 3, the adjusted fresh LBR was 38% lower than its subsequent frozen transfer LBR (OR = 0.62 [0.41-0.93]); this was a statistically significant difference, which was not observed in Group 1 (OR = 0.85 [0.56-1.27]) or Group 2 (OR = 0.95 [0.64-1.41]). LIMITATIONS, REASONS FOR CAUTION: This study is a retrospective cohort, with all of the associated inherent biases. WIDER IMPLICATIONS OF THE FINDINGS: Fresh LBR is negatively impacted by a high dose of total FSH used, as compared to the LBR in subsequent paired FET cycles. Frozen transfer LBR seems unaffected by the total FSH dose used in the fresh cycle, suggesting that the endometrium may be adversely affected, probably indirectly, by high dose gonadotropin use in the fresh IVF cycle only. STUDY FUNDING/COMPETING INTEREST(S): No funding source was used for the completion of this project. There are no conflicts of interest.

Severe ovarian hyperstimulation syndrome after combined GnRH-agonist and low-dose human chorionic gonadotropin trigger in a patient with a single kidney.

Ovarian hyperstimulation syndrome (OHSS) following gonadotropin-releasing hormone agonist (GnRH-a) trigger is rare. Here, we report a case of severe OHSS after combined GnRH-a and low-dose human chorionic gonadotropin (hCG) trigger in a patient with a single kidney. The patient is a 32-year-old women with a two-year history of infertility. The patient's history was significant for a single kidney, that is, she had donated a kidney to a family member three years ago. The patient underwent controlled ovarian stimulation (COS) for in vitro fertilization (IVF) and received a combined 2 mg GnRH-a and 1500 IU hCG ovulatory trigger. Estradiol (E2) levels on the day of and after the trigger were 3800 pg/mL and 4001 pg/mL, respectively. Four days after the trigger, the patient began experiencing nausea, abdominal distention and dyspnea, and her blood testing revealed hemoconcentration (hemoglobin: 16.9 g/dL; hematocrit: 51.0%) and an elevated creatinine level (1.16 mg/dL). Fresh embryo transfer was deferred. The patient was admitted to the hospital for fluid monitoring and prophylactic anticoagulation. Following inpatient management, her hemoglobin, hematocrit and creatinine levels normalized. The current report highlights that the systemic effects of OHSS can be accentuated in patients with preexisting renal disease or a single kidney.

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).

BACKGROUND: Pharmacokinetic 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. METHODS: This 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/m(2) 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. RESULTS: Similar 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. CONCLUSIONS: Ovaleap® 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 REGISTRATION: EudraCT: 2009-017674-20. Current controlled trials: ISRCTN74772901 . Date of trial registration: 19 March 2010.

Safety and efficacy of Ovaleap® (recombinant human follicle-stimulating hormone) for up to 3 cycles in infertile women using assisted reproductive technology: a phase 3 open-label follow-up to Main Study.

BACKGROUND: Ovaleap® (follitropin alfa), a recombinant human follicle-stimulating hormone intended for use in controlled ovarian stimulation in women undergoing assisted reproductive technologies (ART), showed therapeutic equivalence to Gonal-f® in a multinational, multicenter, randomized, controlled, assessor-blind phase 3 Main Study. The current study examined safety, including immunogenicity, and efficacy of Ovaleap® in an open-label, uncontrolled, follow-up treatment period of up to 2 additional treatment cycles in patients who did not become pregnant in the phase 3 Main Study. METHODS: Patients with negative biochemical or clinical pregnancy in the phase 3 Main Study, regardless of treatment group (ie, Ovaleap® or Gonal-f®), were eligible to participate. Patients received Ovaleap® (Merckle Biotec GmbH, Ulm, Germany) for up to 2 additional cycles, administered using a reusable semi-automated pen device. The primary objective was the assessment of safety, including adverse events (AEs), ovarian hyperstimulation syndrome (OHSS), and anti-drug antibodies. Tolerability, patient satisfaction with the Ovaleap® pen device, and efficacy outcomes (as evaluated in the Main Study) were also assessed. RESULTS: One hundred forty-seven patients were included in cycle 2, and 61 patients were included in cycle 3. In cycles 2 and 3, 10.9 % (16/147) and 6.6 % (4/61) of patients experienced treatment-emergent AEs (TEAEs), respectively. Three serious TEAEs (ie, appendicitis, OHSS, and borderline ovarian tumor) were reported and successfully resolved. The OHSS TEAE was the only OHSS reported in the study (0.7 % [1/147]). Positive findings on anti-drug antibody assays in 6 serum samples did not show neutralizing activity or clinical relevance in biochemical pregnancy rate. No hypersensitivity reaction occurred. Most patients reported "very good"/"good" local tolerability. All patients were "very confident"/"confident" about dose accuracy and correctness of the injection. They all found use of the pen "very convenient"/"convenient" and were all "very satisfied"/"satisfied" with the pen device. Efficacy outcomes were consistent with the phase 3 Main Study. CONCLUSIONS: These findings further support the safety, including immunogenicity, and efficacy of Ovaleap® for stimulation of follicular development in infertile women undergoing ART. The findings support continued use of Ovaleap® for multiple cycles or a switch to Ovaleap® if pregnancy is initially not achieved with Gonal-f®. TRIAL REGISTRATION: EudraCT number: 2009-017674-20. Current controlled trials register number: ISRCTN74772901 .

When the right (Drug) should be left: Prenatal drug exposure and heterotaxy syndrome.

BACKGROUND: Recent studies reported an association between prenatal propylthiouracil exposure and birth defects, including abnormal arrangement across the left-right body axis, suggesting an association with heterotaxy syndrome. METHODS: This case-control and case-finding study used data from 1981 to 2013 from the EUROCAT birth defect registry in the Northern Netherlands. First, we explored prenatal exposures in heterotaxy syndrome (cases) and Down syndrome (controls). Second, we describe the specific birth defects in offspring of mothers using propylthiouracil (PTU) prenatally. RESULTS: A total of 66 cases with heterotaxy syndrome (incidence 12.1 per 100,000 pregnancies) and 783 controls with Down syndrome (143.3 per 100,000 pregnancies) were studied. No differences in intoxication use during pregnancy were found between cases and controls, including smoking (28.0% vs. 22.7%; p = 0.40), alcohol (14.0% vs. 26.9%; p = 0.052), and recreational drugs (0 vs. 0.3%; p = 1.00). We found an association between heterotaxy syndrome and prenatal drug exposure to follitropin-alfa (5.6% vs. 1.1%; p = 0.04), and drugs used in nicotine dependence (3.7% vs. 0.2%; p = 0.02). Five mothers used PTU during pregnancy and gave birth to a child with trisomy 18, renal abnormalities, or hypospadias and cardiac defects. CONCLUSION: This study identified follitropin-alfa and drugs used in nicotine dependence as possible teratogens of heterotaxy syndrome. Our data suggest the possibility that there is an increased risk of birth defects (including renal, urological, and cardiac abnormalities) in children born among mothers taking PTU prenatally, but not for heterotaxy syndrome. Birth Defects Research (Part A) 106:573-579, 2016. © 2016 Wiley Periodicals, Inc.

Selective use of corifollitropin for controlled ovarian stimulation for IVF in patients with low anti-Müllerian hormone.

Corifollitropin, a long-acting follicle-stimulating hormone (FSH) analogue used for in vitro fertilization (IVF), does not allow individualization of dosage, and the ovarian response is similar to around 300 IU of daily recombinant FSH. This has raised concerns about the risk of ovarian hyperstimulation syndrome (OHSS) when used in standard patients. We administered corifollitropin selectively to patients with anticipated low to moderate ovarian response based on antimüllerian hormone levels in the lower quartile. The end points were oocyte distribution and occurrence of OHSS in women with AMH ≤15 pmol/L. The study included a cohort of 368 patients treated in 599 cycles. Post hoc the cohort was subdivided according to AMH. With increasing baseline AMH, the number of oocytes increased from a mean of 2.7 (range 0-8 with AMH <3 pmol/L) to 6.3 (range 0-15 with AMH 10-15 pmol/L) oocytes. Cancellations of retrievals and transfers decreased significantly with increasing AMH. Overall, the ongoing live pregnancy rate per started cycle was 15.2%. None developed OHSS. No cycles were cancelled or needed triggering of ovulation using a GnRH agonist due to risk of OHSS. Selective use of corifollitropin in patients with AMH in the lower quartile is a safe and appropriate way of optimising stimulation.

Very unusual symptoms consistent with a possible migraine immediately following the injection of recombinant follitropin beta.

PURPOSE: To present a new side effect of follitropin beta not shared with highly purified urinary follicle stimulating honnone (FSH). MATERIALS AND METHODS: Follitropin beta was administered for preparation of in vitro fertilization-embryo transfer (IVF-ET). RESULTS: Within a few minutes of injection of subcutaneously of follitropin beta, a 27-year-old woman developed a feeling of fever, headache, nausea, vomiting dizziness, and a visual aura consistent with migraine syndrome. These side effects did not occur when switched to highly purified urinary FSH. CONCLUSIONS: Since this reaction did not occur when injected with FSH not made with recombinant DNA technology, it is concluded that recombinant FSH (at least with follitropin beta) can produce an immediate migraine-like syndrome.

Patient preference for a long-acting recombinant FSH product in ovarian hyperstimulation in IVF: a discrete choice experiment.

STUDY QUESTION: What factors or attributes of a long-acting recombinant FSH (rFSH) or daily-administrated rFSH influence women's preferences IVF? SUMMARY ANSWER: Patients' preferences for rFSH products are primary influenced by the attribute 'number of injections', but a low 'number of injections' is exchanged for a high 'number of injections' at a 6.2% decrease in 'risk of cycle cancellation due to low response' and at a 4.5% decrease in 'chance of OHSS'. WHAT IS KNOWN ALREADY: Injections of long-acting rFSH have been claimed to be preferred over daily-administrated rFSH injections, but patient preference studies to underpin this assumption have not been performed. STUDY DESIGN, SIZE, DURATION: A discrete choice experiment (DCE) was created to assess women's preference for long-acting or daily-administrated rFSH under varying attributes of efficiency, safety and burden. The selected attributes were the 'total number of injections', 'chance of ovarian hyperstimulation syndrome (OHSS)' and the 'risk of cycle cancellation due to low response'. Questionnaires were handed out during information gathering sessions in one academic hospital and two teaching hospitals in The Netherlands between April 2011 and April 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women at the start of their first IVF treatment were asked to participate in this patient preference study. Participation was voluntary. We analysed the data by using mixed logit models to estimate the utility of each attribute. MAIN RESULTS AND THE ROLE OF CHANCE: Questionnaires (n = 125) were handed out with a response rate of 77% (97/125). Four respondents did not complete the questionnaire. Hence, there were 93 questionnaires available for analysis. All attributes significantly influenced women's preference. Overall, the lower 'number of injections' was preferred above the higher 'number of injections' (mean coefficient 1.25; P < 0.001), while an increase of 1% in 'chance of OHSS' or 5% 'risk of cycle cancellation due to low response' was non-preferred (mean coefficients -0.31 and -0.24, respectively, P < 0.01). The majority of respondents was willing to trade-off a lower 'number of injections' for a higher 'number of injections' when gaining a 6.2% reduction in 'cycle cancellation due to low response', or a 4.5% reduction in 'chance of OHSS'. LIMITATIONS, REASONS FOR CAUTION: The generalizability of this DCE is limited in time-span. Women may choose differently when they have previous experience with long-acting rFSH, or when they have to pay for the medication, hospital visits and treatments themselves. WIDER IMPLICATIONS OF THE FINDINGS: The results of this DCE helps us to understand the trade-off women make in their preference for a long-acting rFSH product or a daily-administrated rFSH product in IVF and may support doctors when counselling patients.

Corifollitropin alfa compared with follitropin beta in poor responders undergoing ICSI: a randomized controlled trial.

STUDY QUESTION: Does substituting 150 µg corifollitropin alfa for 450 IU follitropin beta during the first 7 days of ovarian stimulation in proven poor responders, result in retrieval of a non-inferior number (<1.5 fewer) of cumulus oocyte complexes (COCs)? SUMMARY ANSWER: A single s.c. dose of 150 µg corifollitropin alfa on the first day of ovarian stimulation, followed if necessary, from Day 8 onwards, with 450 IU of follitropin beta/day, is not inferior to daily doses of 450 IU follitropin beta. The 95% CI of the difference between medians in the number of oocytes retrieved was -1 to +1 within the safety margin of 1.5. WHAT IS KNOWN ALREADY: Recent data from retrospective studies suggest that the use of corifollitropin alfa in poor responders is promising since it could simplify ovarian stimulation without compromising its outcome. STUDY DESIGN, SIZE, DURATION: Seventy-nine women with previous poor ovarian response undergoing ICSI treatment were enrolled in this open label, non-inferiority, randomized clinical trial (RCT). PARTICIPANTS/MATERIALS, SETTING, METHODS: Inclusion criteria were: previous poor response to ovarian stimulation (≤4 COCs) after maximal stimulation, age <45 years, regular spontaneous menstrual cycle, body mass index: 18-32 kg/m(2) and basal follicle stimulating hormone ≤20 IU/l. On Day 2 of the menstrual cycle, patients were administered either a single s.c dose of 150 µg corifollitropin alfa (n = 40) or a fixed daily dose of 450 IU of follitropin beta (n = 39). In the corifollitropin alfa group, 450 IU of follitropin beta were administered from Day 8 of stimulation until the day of human chorionic gonadotrophin (hCG) administration, if necessary. To inhibit premature luteinizing hormone surge, the gonadotrophin releasing hormone antagonist ganirelix was used. Triggering of final oocyte maturation was performed using 250 µg of recombinant hCG, when at least two follicles reached 17 mm in mean diameter. MAIN RESULTS AND THE ROLE OF CHANCE: The number of COCs retrieved was not statistically different between the corifollitropin alfa and the follitropin beta groups [Median 3 versus 2, 95% CI 2-4, 2-3, respectively, P = 0.26]. The 95% CI of the difference between medians in the number of oocytes retrieved was -1 to +1. A multivariable analysis adjusting for all the potential baseline differences confirmed this finding. No significant difference was observed regarding the probability of live birth between the corifollitropin alfa and the follitropin beta group (live birth per patient reaching oocyte retrieval: 7.9 versus 2.6%, respectively, difference +5.3%, 95% CI: -6.8 to +18.3). LIMITATIONS, REASONS FOR CAUTION: The present study was not powered to test a smaller difference (e.g. 1 COC) in terms of COCs retrieved as well as to show potential differences in the probability of pregnancy. Moreover, it would be interesting to assess whether the continuation of stimulation in the long acting FSH arm, where necessary, with 200 IU instead of 450 IU of follitropin beta would have altered the direction or the magnitude of the effect of the type of FSH, observed on the number of COCs retrieved. WIDER IMPLICATIONS OF THE FINDINGS: Corifollitropin alfa simplifies IVF treatment because it is administered in a GnRH antagonist protocol and replaces seven daily FSH injections with a single one of a long acting FSH without compromising the outcome. It could greatly reduce the burden of treatment for poor responders and this deserves further investigation.

Phase I, two-way, crossover study to demonstrate bioequivalence and to compare safety and tolerability of single-dose XM17 vs Gonal-f® in healthy women after follicle-stimulating hormone downregulation.

BACKGROUND: XM17 is a recombinant human follicle-stimulating hormone (rhFSH) intended mainly for use in controlled ovarian hyperstimulation and the treatment of anovulation. The purpose of the current study was to establish bioequivalence, safety and tolerability of single 300-IU subcutaneous (sc) doses of XM17 to that of the reference follitropin alfa (Gonal-f(®)) in healthy young women. METHODS: This open-label, Phase I, single-dose, single-center, two-way crossover study was conducted from February to May 2009. Thirty-six women aged 18-39 years were included, with a study duration of ~27 days per participant. After endogenous FSH downregulation with goserelin (3.6 mg) on study Day 0, XM17 and Gonal-f(®) were administered on Days 11 and 19 in random sequence. Frequent serum samples were drawn for standard pharmacokinetics until 168 h postdosing. Laboratory values, adverse events (AEs) and local tolerability were assessed throughout the study period. Primary endpoints included Cmax and AUC0-t. Secondary endpoints included additional pharmacokinetic (PK) parameters, safety and tolerability. RESULTS: Ratios of XM17 to Gonal-f(®) for Cmax and AUC0-t equaled 1.017 (90 % confidence interval [CI]: 0.958, 1.080) and 1.028 (90 % CI: 0.931, 1.134), respectively, with the CIs contained within the predefined interval (0.8, 1.25). Ratios for AUC0-168h, AUC0-∞ and t1/2 were also ~1, and no difference in tmax was detected. Both XM17 and Gonal-f(®) were well tolerated, with no detectable anti-FSH antibodies, serious AEs or AEs leading to discontinuation or dose reduction. CONCLUSIONS: PK bioequivalence of single 300-IU sc doses of XM17 to the reference product Gonal-f® was statistically demonstrated. XM17 was well tolerated both systemically and locally. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02592031 ; date of registration: 28 October, 2015.

Randomized, controlled, open-label, non-inferiority study of the CONSORT algorithm for individualized dosing of follitropin alfa.

In this randomized, controlled, open-label, phase IV study, ovarian response after a follitropin alfa starting dose determined by the CONSORT calculator was compared with a standard dose (150 IU). Normo-ovulatory women (aged 18-34 years) eligible for assisted reproductive techniques were recruited (23 centres: nine European countries and Chile); 200 women were randomized (CONSORT [n = 96]; standard dosing [n = 104]). Significantly lower mean daily (121.5 versus 167.4 IU; P < 0.001) and total (1288.5 versus 1810.0 IU; P < 0.001) doses of follitropin alfa were administered in the CONSORT group. Clinical pregnancy rates were CONSORT (36.0%) and standard dosing (35.5%); estimated difference (confidence interval 0.6%; -13.5 to 14.6). Ovarian hyperstimulation syndrome occurred in 6.3% and 12.5% of patients in the CONSORT and standard-dosing groups, respectively. The primary efficacy analysis found a significantly lower mean [SD] number of oocytes retrieved in the CONSORT (10.0 [5.6]; P = 0.037) versus standard-dosing group (11.8 [5.3]). Although the CONSORT calculator was statistically inferior to standard dosing in the number of oocytes retrieved, clinical pregnancy rates (fresh embryo transfers) were similar in both groups, and incidence of ovarian hyperstimulation syndrome was lower in the CONSORT group.

Single therapeutic and supratherapeutic doses of corifollitropin alfa, a sustained follicle stimulant, do not prolong the QTcF-interval in healthy postmenopausal volunteers.

OBJECTIVE: Corifollitropin alfa (Elonva®) is the first hybrid follicle-stimulating hormone molecule with demonstrated sustained follicle-stimulating activity after a single subcutaneous injection. This trial evaluated if corifollitropin alfa is associated with QT/QTc prolongation and/ or proarrhythmic potential as compared to placebo in healthy post-menopausal women. MATERIALS: Participants were healthy, postmenopausal women. Study treatments were corifollitropin alfa 150 µg, corifollitropin alfa 240 µg, and moxifloxacin 400 mg with placebo. METHODS: This randomized, double blind, double-dummy, 4-period crossover trial compared single doses of corifollitropin alfa 150 µg (therapeutic dose), corifollitropin alfa 240 µg (supratherapeutic dose), and moxifloxacin 400 mg (positive control) with placebo. Corifollitropin alfa was administered on day 1 and moxifloxacin on day 2. RESULTS: The largest time-matched mean QTcF difference versus placebo for the therapeutic dose of corifollitropin alfa was 1.4 ms (upper limit of 1-sided 95% confidence interval (UL 95% CI) = 3.4 ms), and for the supratherapeutic dose was 1.2 ms (UL 95% CI = 3.6 ms). CONCLUSIONS: For both the therapeutic and the supratherapeutic dose of corifollitropin alfa and at all time points, the UL 95% CI for the time matched QTcF differences compared with placebo was below 10 ms, the threshold of relevance defined by the ICH E14 guideline. Single therapeutic and supratherapeutic doses of corifollitropin alfa are not associated with clinically relevant QT/QTc-interval prolongation in healthy post-menopausal women.

Phase IV, open-label, randomized study of low-dose recombinant human follicle-stimulating hormone protocols for ovulation induction.

BACKGROUND: This Phase IV, open-label, multicentre, randomized study (MEnTOR) compared two low-dose recombinant human follicle-stimulating hormone (r-hFSH) protocols for ovulation induction. METHODS: This study was conducted in six Middle Eastern countries between March 2009 and March 2011. Eligible women (18-37 years), with World Health Organization Group II anovulatory infertility, were randomized to receive r-hFSH (starting daily dose: 75 IU) as a chronic low-dose (CLD) (37.5 IU dose increase on Day 14) or low-dose (LD) (37.5 IU dose increase on Day 7) protocol if no follicles were ≥ 10 mm. The maximum r-hFSH daily dose permitted was 225 IU/day. The total length of ovarian stimulation could not exceed 35 days, unless ultrasound assessment suggested imminent follicular growth and maturation. Patients underwent only one treatment cycle. Primary endpoint: incidence of mono-follicular development. Secondary endpoints included: stimulation duration and rates of bi-follicular development; human chorionic gonadotrophin administration rate; clinical pregnancy; and cycle cancellation (owing to inadequate response). Adverse events (AEs) were recorded. The primary efficacy analysis was performed using data from all patients who received at least one dose of correct study medication, had at least one efficacy assessment, and no protocol violations at treatment start (CLD group, n=122; LD group, n=125). RESULTS: Mono-follicular development rates (primary endpoint) were similar in both groups (CLD: 56.6% [69/122] versus LD: 55.2% [69/125], p=0.93; primary efficacy analysis population). Similarly, there were no significant differences between groups in bi-follicular development, clinical pregnancy or cycle cancellation (inadequate response) rates. In patients who received human chorionic gonadotrophin injections, the mean duration of stimulation was 13.7 days in the CLD group and 12.9 days in the LD group. Clinical pregnancy rates for those patients who received an hCG injection were similar in both groups (CLD: 20.2% [19/94] versus LD: 19.8% [18/91], p=0.94; primary efficacy analysis population). Most AEs were mild in severity. Only one case of ovarian hyperstimulation syndrome was reported (mild; CLD group). CONCLUSIONS: Efficacy and safety outcomes were similar for the two protocols.

Human steroidogenesis: implications for controlled ovarian stimulation with exogenous gonadotropins.

In the menstrual cycle, the mid-cycle surge of gonadotropins (both luteinising hormone [LH] and follicle-stimulating hormone [FSH]) signals the initiation of the periovulatory interval, during which the follicle augments progesterone production and begins to luteinise, ultimately leading to the rupture of the follicle wall and the release of an oocyte. The administration of gonadotropins in controlled ovarian stimulation (COS) leads to supraphysiological steroid concentrations of a very different profile compared with those seen during natural cycles. It has been suggested that these high steroid concentrations cause alterations in endometrial development, affecting oocyte viability in assisted reproductive technology. Furthermore, it has been proposed that elevated progesterone levels have a negative effect on the reproductive outcome of COS. This may arise from an asynchrony between embryo stage and endometrium status at the window of implantation. The regulation of progesterone production by the developing follicles during COS is a complicated interplay of hormonal systems involving the theca and granulosa cells, and the effect of the actions of both LH and FSH. The present paper reviews current knowledge of the regulation of progesterone in the human ovary during the follicular phase and highlights areas where knowledge remains limited. In this review, we provide in-depth information outlining the regulation and function of gonadotropins in the complicated area of steroidogenesis. Based on current evidence, it is not clear whether the high levels of progesterone produced during COS have detrimental effects on fertility.

The rate of high ovarian response in women identified at risk by a high serum AMH level is influenced by the type of gonadotropin.

The aim was to compare ovarian response and clinical outcome of potential high-responders after stimulation with highly purified menotropin (HP-hMG) or recombinant follicle-stimulating hormone (rFSH) for in vitro fertilisation/intracytoplasmic sperm injection. Retrospective analysis was performed on data collected in two randomized controlled trials, one conducted following a long GnRH agonist protocol and the other with an antagonist protocol. Potential high-responders (n = 155 and n = 188 in the agonist and antagonist protocol, respectively) were defined as having an initial anti-Müllerian hormone (AMH) value >75th percentile (5.2 ng/ml). In both protocols, HP-hMG stimulation in women in the high AMH category was associated with a significantly lower occurrence of high response (≥15 oocytes retrieved) than rFSH stimulation; 33% versus 51% (p = 0.025) and 31% versus 49% (p = 0.015) in the long agonist and antagonist protocol, respectively. In the potential high-responder women, trends for improved live birth rate were observed with HP-hMG compared with rFSH (long agonist protocol: 33% versus 20%, p = 0.074; antagonist protocol: 34% versus 23%, p = 0.075; overall population: 34% versus 22%, p = 0.012). In conclusion, the type of gonadotropin used for ovarian stimulation influences high-response rates and potentially clinical outcome in women identified as potential high-responders.