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

Ishihara, Osamu; Arce, Joan‐Carles

doi:10.1016/j.rbmo.2021.01.023

Cited by 42 publications

(85 citation statements)

References 29 publications

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“…The current study is the first RCT investigating the use of individualised gonadotropin dosing in Asian IVF/ICSI patients and adequately powered for pregnancy outcomes. It demonstrated the efficacy and safety of follitropin delta in Asian women undergoing ovarian stimulation, and clinically validated the appropriateness of the individualised follitropin delta fixed-dose regimen in a wider Asian population beyond the confirmation already reported for Japanese patients ( Ishihara and Arce, 2021 ). In addition to establishing non-inferiority of individualised follitropin delta to conventional follitropin alfa with respect to the primary endpoint of ongoing pregnancy rate, the present trial furthermore showed that the individualised follitropin delta dosing approach has the potential for efficacy benefits beyond the recognised advantages in safety and treatment efficiency ( Nyboe Andersen and Nelson et al , 2017 ; Bosch et al , 2019 ; Ishihara and Arce, 2021 ).…”

Section: Discussionmentioning

confidence: 52%

“…It demonstrated the efficacy and safety of follitropin delta in Asian women undergoing ovarian stimulation, and clinically validated the appropriateness of the individualised follitropin delta fixed-dose regimen in a wider Asian population beyond the confirmation already reported for Japanese patients ( Ishihara and Arce, 2021 ). In addition to establishing non-inferiority of individualised follitropin delta to conventional follitropin alfa with respect to the primary endpoint of ongoing pregnancy rate, the present trial furthermore showed that the individualised follitropin delta dosing approach has the potential for efficacy benefits beyond the recognised advantages in safety and treatment efficiency ( Nyboe Andersen and Nelson et al , 2017 ; Bosch et al , 2019 ; Ishihara and Arce, 2021 ). Women using the individualised follitropin delta dosing regimen achieved significantly higher live birth rates compared to the women treated with a conventional dosing regimen; a trend observed already for the earlier pregnancy parameter of positive βhCG rate.…”

Section: Discussionmentioning

confidence: 52%

“…Follitropin delta is a novel recombinant FSH (rFSH) preparation expressed in a human cell line (PER.C6 ® ) and developed with an individualised dosing regimen based on each woman’s serum anti-Müllerian hormone (AMH) concentration and body weight in an effort to guide clinicians to achieve an ovarian response that can minimise the risk of ovarian hyperstimulation syndrome (OHSS) without compromising efficacy. Two randomised controlled trials (RCTs) have shown that the individualised follitropin delta dosing regimen, through modulation of the ovarian response, can reduce the OHSS risk versus other rFSH preparations, while providing at least the same live birth rates ( Nyboe Andersen and Nelson et al , 2017 ; Ishihara and Arce, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Although a trial has been performed in Japanese women ( Ishihara and Arce, 2021 ), most of the data validating the individualised dosing approach are from a large trial conducted in predominantly Caucasian women ( Nyboe Andersen and Nelson et al , 2017 ). Therefore, the aim of this large, randomised, controlled study was to investigate follitropin delta in its novel individualised algorithm-based dosing regimen in the Asian patient population, and to compare its efficacy and safety to follitropin alfa in its recommended conventional dosing approach.…”

Section: Introductionmentioning

confidence: 99%

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A randomised controlled trial to clinically validate follitropin delta in its individualised dosing regimen for ovarian stimulation in Asian IVF/ICSI patients

et al. 2021

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STUDY QUESTION Is ovarian stimulation with follitropin delta in its individualised fixed-dose regimen at least as efficacious as follitropin alfa in a conventional dosing regimen in Asian population? SUMMARY ANSWER Ovarian stimulation with individualised follitropin delta dosing resulted in a non-inferior ongoing pregnancy rate, a significantly higher live birth rate and a significantly lower incidence of early ovarian hyperstimulation syndrome (OHSS) and/or preventive interventions compared to conventional follitropin alfa dosing. WHAT IS KNOWN ALREADY Previous randomised controlled trials conducted in Japan as well as in Europe, North- and South America have demonstrated that ovarian stimulation with the individualised follitropin delta dosing regimen based on serum anti-Müllerian hormone (AMH) level and body weight modulated the ovarian response and reduced the risk of OHSS without compromising pregnancy and live birth rates. STUDY DESIGN, SIZE, DURATION Randomised, controlled, multi-centre, assessor-blind trial conducted in 1009 Asian patients from mainland China, South Korea, Vietnam and Taiwan, undergoing their first IVF/ICSI cycle. Randomisation was stratified by age (<35, 35–37, 38–40 years). The primary endpoint was ongoing pregnancy rate assessed 10–11 weeks after embryo transfer in the fresh cycle (non-inferiority limit −10.0%; analysis adjusted for age stratum). PARTICIPANTS/MATERIALS, SETTING, METHODS The follitropin delta treatment consisted of a fixed daily dose individualised according to each patient’s initial AMH level and body weight (AMH <15 pmol/l: 12 μg; AMH ≥15 pmol/l: 0.19 to 0.10 μg/kg; min-max 6–12 μg). The follitropin alfa dose was 150 IU/day for the first 5 days with subsequent potential dose adjustments according to individual response. A GnRH antagonist protocol was applied. OHSS was classified based on Golan’s system. Women with an ongoing pregnancy were followed until live birth and 4 weeks after. MAIN RESULTS AND THE ROLE OF CHANCE The number of oocytes retrieved was significantly (P < 0.001) lower with individualised follitropin delta versus conventional follitropin alfa (10.0 ± 6.1 versus 12.4 ± 7.3). Nevertheless, compared to the conventional dosing approach, the individualised follitropin delta dosing regimen resulted in on average 2 more oocytes (9.6 ± 5.3 versus 7.6 ± 3.5) in potential low responders as indicated by AMH <15 pmol/l, and on average 3 fewer oocytes (10.1 ± 6.3 versus 13.8 ± 7.5) in potential high responders as indicated by AMH ≥15 pmol/l. Among women with AMH ≥15 pmol/l, excessive response occurred less frequently with individualised follitropin delta than with follitropin alfa (≥15 oocytes: 20.2% versus 39.1%; ≥20 oocytes: 6.7% versus 18.5%; both P < 0.001). The incidence of early OHSS and/or preventive interventions for early OHSS was significantly (P = 0.004) reduced from 9.6% with follitropin alfa to 5.0% with individualised follitropin delta. The total gonadotropin use was significantly (P < 0.001) reduced from an average of 109.9 ± 32.9 μg (1498 ± 448 IU) follitropin alfa to 77.5 ± 24.4 μg follitropin delta. Non-inferiority of follitropin delta in its individualised dosing regimen to conventional follitropin alfa was established with respect to the primary endpoint of ongoing pregnancy rate which was 31.3% with follitropin delta compared to 25.7% with follitropin alfa (estimated mean difference 5.4% [95% CI: −0.2%; 11.0%]). The live birth rate was significantly higher at 31.3% with individualised follitropin delta compared to 24.7% with follitropin alfa (estimated mean difference 6.4% [95% CI: 0.9%; 11.9%]; P = 0.023). The live birth rate for each stratum were as follows for follitropin delta and follitropin alfa, respectively; <35 years: 31.0% versus 25.0%, 35–37 years: 35.3% versus 26.7%, 38–40 years: 20.0% versus 14.3%. LIMITATIONS, REASONS FOR CAUTION The trial only covered the clinical outcome of one treatment cycle with fresh cleavage-stage embryo transfers. WIDER IMPLICATIONS OF THE FINDINGS The present trial shows that in addition to reducing the early OHSS risk, follitropin delta in its individualised fixed-dose regimen has the potential to improve the success rate in fresh cycles across all ages and with a lower gonadotropin consumption compared to conventional follitropin alfa dosing. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by Ferring Pharmaceuticals. J.Q., Y.Z., X.L., T.H., H.-Y.H. and S.-H.K. have received institutional (not personal) clinical trial fees from Ferring Pharmaceuticals. M.G., B.M. and J.-C.A. are employees of Ferring Pharmaceuticals. J.-C.A. has pending and issued patent applications in the WO 2013/020996 and WO 2019/043143 patent families that comprise allowed and granted patent rights related to follitropin delta. TRIAL REGISTRATION NUMBER NCT03296527 (clinicaltrials.gov). TRIAL REGISTRATION DATE 28 September 2017 DATE OF FIRST PATIENT’S ENROLMENT 1 December 2017

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A randomised controlled trial to clinically validate follitropin delta in its individualised dosing regimen for ovarian stimulation in Asian IVF/ICSI patients

et al. 2021

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“…Comprehensive clinical trials have been performed in in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) patients undergoing ovarian stimulation to document the efficacy and safety of follitropin delta versus CHO-derived recombinant FSH preparations [8][9][10][11][12][13]. The trials have mainly focused on fresh cycles and have provided reassuring information on follitropin delta with respect to the clinical performance of fresh blastocysts leading to pregnancy and live birth as well as the safety of the patients.…”

Section: Introductionmentioning

confidence: 99%

Pregnancy and neonatal outcomes in fresh and frozen cycles using blastocysts derived from ovarian stimulation with follitropin delta

Havelock

Henningsen

Mannaerts

et al. 2021

J Assist Reprod Genet

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Purpose To describe the pregnancy and neonatal outcomes using fresh and vitrified/warmed blastocysts obtained from ovarian stimulation with follitropin delta in controlled trials versus follitropin alfa. Methods This investigation evaluated the outcome from 2719 fresh and frozen cycles performed in 1326 IVF/ICSI patients who could start up to three ovarian stimulations in the ESTHER-1 (NCT01956110) and ESTHER-2 (NCT01956123) trials, covering 1012 fresh cycles and 341 frozen cycles with follitropin delta and 1015 fresh cycles and 351 frozen cycles with follitropin alfa. Of the 1326 first cycle patients, 513 continued to cycle 2 and 188 to cycle 3, and 441 patients started frozen cycles after the fresh cycles. Pregnancy follow-up was continued until 4 weeks after birth. Results The overall cumulative take-home baby rate after up to three stimulation cycles was 60.3% with follitropin delta and 60.7% with follitropin alfa (−0.2% [95% CI: −5.4%; 5.0%]), of which the relative contribution was 72.8% from fresh cycles and 27.2% from frozen cycles in each treatment group. Across the fresh cycles, the ongoing implantation rate was 32.1% for follitropin delta and 32.1% for follitropin alfa, while it was 27.6% and 27.8%, respectively, for the frozen cycles. Major congenital anomalies among the live-born neonates up until 4 weeks were reported at an incidence of 1.6% with follitropin delta and 1.8% with follitropin alfa (−0.2% [95% CI: −1.9%; 1.5%]). Conclusions Based on comparative trials, the pregnancy and neonatal outcomes from fresh and frozen cycles provide reassuring data on the efficacy and safety of follitropin delta. Trial registration ClinicalTrials.gov Identifier: NCT01956110 registered on 8 October 2013; NCT01956123 registered on 8 October 2013.

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Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI)

Ngwenya,

Lensen,

Vail

et al. 2024

Cochrane Database of Systematic Reviews

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

Cited by 42 publications

References 29 publications

A randomised controlled trial to clinically validate follitropin delta in its individualised dosing regimen for ovarian stimulation in Asian IVF/ICSI patients

A randomised controlled trial to clinically validate follitropin delta in its individualised dosing regimen for ovarian stimulation in Asian IVF/ICSI patients

Pregnancy and neonatal outcomes in fresh and frozen cycles using blastocysts derived from ovarian stimulation with follitropin delta

Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI)

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