STUDY QUESTION: Does addition of choriogonadotropin beta (recombinant CG beta) to follitropin delta increase the number of good-quality blastocysts following ovarian stimulation in a long GnRH agonist protocol? SUMMARY ANSWER: At the doses investigated, the addition of CG beta reduced the number of intermediate follicles and related down-stream parameters including the number of oocytes and blastocysts. WHAT IS KNOWN ALREADY: CG beta is a novel recombinant hCG (rhCG) molecule expressed by a human cell line (PER.C6®) and has a different glycosylation profile compared to urinary hCG or rhCG derived from a Chinese Hamster Ovary (CHO) cell line. In the first-in-human trial, the CG beta pharmacokinetics were similar between men and women. In women, the AUC and the peak serum concentration (Cmax) increased approximately dose proportionally following single and multiple daily doses. In men, a single dose of CG beta provided higher exposure with a longer half-life and proportionately higher testosterone production than CHO cell-derived rhCG. STUDY DESIGN, SIZE, DURATION: This placebo-controlled, double-blind, randomized trial (RAINBOW) was conducted in five European countries to explore the efficacy and safety of CG beta as add-on treatment to follitropin delta in women undergoing ovarian stimulation in a long GnRH agonist protocol. Randomization was stratified by centre and age (30-37 and 38-42 years). The primary endpoint was the number of good-quality blastocysts (Grade 3 BB or higher). Subjects were randomized to receive either placebo or 1, 2, 4, 8 or 12 μg CG beta added to the daily individualized follitropin delta dose during ovarian stimulation. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 620 women (30-42 years) with anti-Müllerian hormone (AMH) levels between 5 and 35 pmol/l were randomized in equal proportions to the six treatment groups and 619 subjects started treatment. All 619 subjects were treated with an individualized dose of follitropin delta determined based on AMH (Elecsys AMH Plus Immunoassay) and body weight. Triggering with rhCG was performed when 3 follicles were ≥17 mm but no more than 25 follicles ≥12 mm were reached. MAIN RESULTS AND THE ROLE OF CHANCE: The demographic characteristics were comparable between the six treatment groups and the overall mean age, body weight and AMH were 35.6 ± 3.3 years, 65.3 ± 10.7 kg and 15.3 ± 7.0 pmol/l, respectively. The incidence of cycle cancellation (range 0-2.9%), total follitropin delta dose (mean 112 μg) and duration of stimulation (mean 10 days) were similar across the groups. At stimulation Day 6, the number and size of follicles was similar between the treatment groups, whereas at the end-of-stimulation dose-related decrease of the intermediate follicles between 12 and 17 mm was observed in comparison to the placebo group. In contrast, the number of follicles ≥17 mm was similar between the CG beta dose groups and the placebo group. A reduced number of intermediate follicles (12 to 17 mm) and fewer oocytes (mean range 9.7 to 11.2) were observed for all doses of CG beta compared to the follitropin delta only group (mean 12.5). The mean number of good-quality blastocysts was 3.3 in the follitropin delta group and ranged between 2.1 and 3.0 across the CG beta groups. The incidence of transfer cancellation was higher in the 4, 8 and 12 μg group, mostly as no blastocyst was available for transfer. In the group receiving only follitropin delta, the ongoing pregnancy rate (10-11 weeks after transfer) was 43% per started cycle versus 28-39% in CG beta groups and 49% per transfer versus 38-50% in the CG beta groups. There was no apparent effect of CG beta on the incidence of adverse events, which was 48.1% in the placebo group and 39.6-52.3% in the CG beta dose groups. In line with the number of collected oocytes, the overall ovarian hyperstimulation syndrome incidence remained lower following follitropin delta with CG beta (2.0-10.3%) compared with follitropin delta only treatment (11.5%). Regardless of the dose, CG beta was safe and well-tolerated with low risk of immunogenicity. LIMITATIONS, REASONS FOR CAUTION: The effect of the unique glycosylation of CG beta and its associated potency implications in women were not known prior to this trial. Further studies will be needed to evaluate optimal doses of CG beta for this and/or different indications. WIDER IMPLICATIONS OF THE FINDINGS: The high ongoing pregnancy rate in the follitropin delta group supports the use of individualized follitropin delta dosing in a long GnRH agonist protocol. The addition of CG beta reduced the presence of intermediate follicles with the investigated doses and negatively affected all down-stream parameters. Further clinical research will be needed to assess the optimal dose of CG beta in the optimal ratio to follitropin delta to develop this novel combination product containing both FSH and LH activity for ovarian stimulation. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by Ferring Pharmaceuticals, Copenhagen, Denmark. B.M. and P.L. are employees of Ferring Pharmaceuticals. M.F.S., H.V., C.Y.A., M.F., C.B., A.P. and Y.K. have received institutional clinical trial fees from Ferring Pharmaceuticals. C.B. has received payments for lectures from Organon, Ferring Pharmaceuticals, Merck A/S and Abbott. M.F.S. has received payment for lectures from Ferring Pharmaceuticals. Y.K. has received payment for lectures from Merck and travel support from Gedeon Richter. H.V. has received consulting fees from Oxo and Obseva and travel support from Gedeon Richter, Ferring Pharmaceuticals and Merck. C.Y.A. has received payment for lectures from IBSA, Switzerland. M.F and C.Y.A. were reimbursed as members of the Data Monitoring Board in this trial. M.F. has an issued patent about unitary combination of FSH and hCG (EP1633389). TRIAL REGISTRATION NUMBER: 2017-003810-13 (EudraCT Number). TRIAL REGISTRATION DATE: 21 May 2018. DATE OF FIRST PATIENT’S ENROLMENT: 13 June 2018.
- MeSH
- Anti-Mullerian Hormone MeSH
- CHO Cells MeSH
- Chorionic Gonadotropin MeSH
- Cricetulus MeSH
- Fertilization in Vitro methods MeSH
- Follicle Stimulating Hormone, Human * MeSH
- Gonadotropin-Releasing Hormone MeSH
- Ovulation Induction * methods MeSH
- Cricetinae MeSH
- Pharmaceutical Preparations MeSH
- Humans MeSH
- Chorionic Gonadotropin, beta Subunit, Human MeSH
- Randomized Controlled Trials as Topic MeSH
- Recombinant Proteins MeSH
- Pregnancy MeSH
- Body Weight MeSH
- Pregnancy Rate MeSH
- Animals MeSH
- Check Tag
- Cricetinae MeSH
- Humans MeSH
- Pregnancy MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Clinical Trial Protocol MeSH
RESEARCH QUESTION: How does the efficacy and safety of individualized follitropin delta dosing compare with conventional dosing for ovarian stimulation in potential high responders? DESIGN: Retrospective analysis of 153 potential high responders identified on the basis of baseline serum anti-Müllerian hormone (AMH) levels above 35 pmol/l, who were originally randomized to an individualized fixed dose of follitropin delta based on AMH and body weight (n = 78) or to a daily starting dose of 150 IU follitropin alfa (n = 75). RESULTS: At the end of stimulation, patients treated with individualized follitropin delta or conventional follitropin alfa had 12.1 ± 7.0 and 18.3 ± 7.0 (P < 0.001) follicles measuring 12 mm or wider, and 27.3% and 62.7% had serum progesterone levels higher than 3.18 nmol/l (P < 0.001), respectively. Overall number of oocytes in these two respective arms was 9.3 ± 6.7 and 17.9 ± 8.7 (P < 0.001), and the ongoing pregnancy rate per started cycle after fresh blastocyst transfer was 28.2% and 24.0%. The risk of ovarian hyperstimulation syndrome (OHSS) for all cases was three times higher in the conventional follitropin alfa arm at 16.0% versus 5.1% with individualized follitropin delta treatment (P = 0.025) and 26.7% versus 7.7% (P = 0.001) for early moderate or severe OHSS, preventive interventions for early OHSS, or both. CONCLUSIONS: Treatment with individualized follitropin delta provides an improved efficacy-safety balance in women with high ovarian reserve, as it normalizes the ovarian response and decreases the risk of OHSS without compromising the chance of pregnancy.
- MeSH
- Anti-Mullerian Hormone blood MeSH
- Adult MeSH
- Fertilization in Vitro methods MeSH
- Follicle Stimulating Hormone, Human administration & dosage MeSH
- Ovulation Induction adverse effects MeSH
- Humans MeSH
- Ovarian Hyperstimulation Syndrome blood etiology MeSH
- Birth Rate MeSH
- Progesterone blood MeSH
- Recombinant Proteins administration & dosage MeSH
- Retrospective Studies MeSH
- Pregnancy MeSH
- Body Weight physiology MeSH
- Pregnancy Rate MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Cíl: Cílem studie CERES (CzEch REkovelle real life Study) bylo shromáždit první zkušenosti s užíváním zcela nového gonadotropinu, vyhodnotit účinnost folitropinu delta v běžné české klinické praxi a srovnat získané výsledky s výstupy studie ESTHER-1. Metodika: Ovariální stimulací individualizovanou denní dávkou folitropinu delta v mikrogramech na základě hladiny antimüllerického hormonu (AMH) a tělesné hmotnosti pacientky (AMH < 15 pmol/ l: fixní dávka 12 µg/ d; AMH > 15 pmol/ l: 0,10–0,19 µg/ kg/ d; max. 12 µg/ d). Výsledky: Celkem bylo zařazeno 85 pacientek ve věku 24–42 let, průměrný věk 32,9 let, průměrná tělesná hmotnost 67,8 kg, průměrná hodnota AMH 23,2 pmol/ l. Bylo zahájeno 85 kontrolovaných ovariálních stimulací s folitropinem delta a 84 odběrů vajíček. U 40 pacientek (47 %) byl optimální zisk počtu vajíček (8–14), 75 pacientek (88 %) mělo embryotransfer, 10 (12 %) nemělo embryo vhodné k transferu. U 65 pacientek byl proveden single embryo transfer, u 10 byla transferována dvě embrya. Počet klinických gravidit byl 37 (43,5 % cPR – clinical pregnancy rate), počet porodů živého bylo plodů 30 (35,3 % LBR – live birth rate). Byly hlášeny tři (3,5 %) časné ovariální hyperstimulační syndromy (OHSS) mírného typu. Hospitalizace související s léčbou byla 0. Závěr: Individualizace ovariální stimulace vede k optimalizaci ovariální odpovědi a při zachování účinnosti zvyšuje bezpečnost léčby cestou snížení incidence OHSS. Výsledky získané u české populace jsou zcela srovnatelné s výstupy velké mezinárodní randomizované zaslepené klinické zkoušky ESTHER-1.
Objective: The aim of the study CERES (CzEch REkovelle real life Study) was to gather experience with the use of a novel gonadotrophine, to evaluate the efficacy of follitropin delta in Czech clinical settings and to compare our results with the clinical trial ESTHER-1. Methods: Individualized follitropin delta daily dose in µg based on the patient's anti-Müllerian hormone (AMH) level and body weight (AMH < 15 pmol/ L: 12 µg/ d; AMH > 15 pmol/ L: 0.10–0.19 µg/ kg/ d; max. 2 µg/ d). Results: A total of 85 women (aged 24–42 years) was included in the study. The average patient's age was 32.9 years, the average body weight was 67.8 kg, and the mean level of AMH was 23.2 pmol/ L. There were initiated 85 controlled ovarian stimulations with follitropin delta and 84 egg collections. Forty patients (47%) had optimal number of retrieved eggs (8–14), 75 patients (88%) had embryotransfer, 10 patients (12%) had no embryo suitable for transfer, 65 patients had single embryo transfer and 10 patients had 2 embryos for transfer. There were reported 37 clinical pregnancies (43.5% cPR – clinical pregnancy rate), 30 live births (35.3% LBR – live birth rate), 3 (3.5%) early moderate ovarian hyperstimulation syndroms (OHSS) and no hospitalization due to the treatment. Conclusion: Individualized ovarian stimulation optimizes ovarian response, maintains treatment efficacy and improves safety by reducing OHSS incidence. The results of the Czech population study are fully comparable with the international, randomized, assessor-blinded trial ESTHER-1.
- Keywords
- studie CERES,
- MeSH
- Anti-Mullerian Hormone MeSH
- Fertilization in Vitro * MeSH
- Follicle Stimulating Hormone, Human MeSH
- Gonadotropins MeSH
- Precision Medicine MeSH
- Ovulation Induction * MeSH
- Humans MeSH
- Multicenter Studies as Topic MeSH
- Ovarian Hyperstimulation Syndrome MeSH
- Prospective Studies MeSH
- Recombinant Proteins MeSH
- Pregnancy MeSH
- Check Tag
- Humans MeSH
- Pregnancy MeSH
- Female MeSH
Cíl studie: Shrnout současné možnosti prevence a terapie ovariálního hyperstimulačního syndromu (OHSS). Metodika: Výběr aktuálních prací a doporučených postupů. Výsledky: V pohledu bezpečnosti a prevence OHSS je výhodnější antagonistický protokol. Pacientky se syndromem polycystických ovarií mnohdy benefitují z pouhého podávání metforminu či letrozolu k indukci ovulace. V případě bezprostředně hrozícího OHSS se doporučuje podávat cabergolin v dávce 0,5 mg 1× denně per os, subkutánně nízkomolekulární heparin v profylaktické dávce a dbát na dostatečnou hydrataci. Za nevhodné lze naopak označit podávání diuretik. V případě punkce ascitu lze provést jeho reinstilaci do cévního řečiště. Závěr: Prezentujeme přehled současných doporučení a postupů v rámci prevence a terapie OHSS.
Objective: To present current possibilities of the prevention and therapy of ovarian hyperstimulation syndrome (OHSS). Methods: Literature and guidelines were researched. Results: From the view of safety and prevention of OHSS, antagonistic protocol is suitable. Patients with syndrome of polycystic ovaries benefit from the use of metformin or letrozole that can be sufficient to induce ovulation. As a treatment of imminent OHSS, it is recommended to administer 0.5 mg of cabergoline per os daily as well as low molecular weight heparin subcutaneously in prophylactic dose and to maintain sufficient fluid intake. Diuretics are strongly discouraged to use. To maintain intravascular volume, drained ascites can be reintroduced. Conclusion: We present a review of current literature and recommendations.
RESEARCH QUESTION: Is individualization of dosing with follitropin delta in sequential ovarian stimulation cycles an effective preventive strategy for ovarian hyperstimulation syndrome risk? If so, for which patients does an individualized strategy provide the greatest OHSS risk reduction and/or the need for additional preventive interventions? DESIGN: A secondary analysis of three ovarian stimulation cycles in IVF/intracytoplasmic sperm injection patients included in one randomized, assessor-blinded trial comparing two recombinant FSH preparations (ESTHER-1, NCT01956110), and a second trial in women undergoing up to two additional cycles (ESTHER-2, NCT01956123). Of 1326 women (aged 18-40 years) randomized and treated with follitropin delta or alfa in cycle 1, 513 continued to cycle 2 and 188 to cycle 3. Follitropin delta and alfa doses were maintained/adjusted according to ovarian response in the previous cycle. RESULTS: Individualized dosing with follitropin delta significantly reduced moderate/severe OHSS and/or preventive interventions (P=0.018) versus conventional dosing with follitropin alfa in patients undergoing up to three ovarian stimulation cycles. The greatest benefit was observed in patients in the highest anti-Müllerian hormone (AMH) quartile (P=0.012). On evaluating separately, individualized dosing with follitropin delta significantly lowered the incidences of moderate/severe OHSS (P=0.036) and preventive interventions (P=0.044) versus follitropin alfa. CONCLUSION: An individualized follitropin delta dosing regimen decreased the risk of moderate/severe OHSS as well as the incidence of preventive interventions versus a conventional follitropin alfa regimen. An analysis per AMH quartile indicated that these statistically significant differences are driven mainly by patients with the highest pretreatment AMH levels.
- MeSH
- Adult MeSH
- Fertilization in Vitro MeSH
- Follicle Stimulating Hormone, Human administration & dosage therapeutic use MeSH
- Ovulation Induction * adverse effects MeSH
- Data Interpretation, Statistical MeSH
- Sperm Injections, Intracytoplasmic MeSH
- Cryopreservation MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Ovarian Hyperstimulation Syndrome prevention & control MeSH
- Ovary drug effects MeSH
- Recombinant Proteins administration & dosage therapeutic use MeSH
- Risk MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
OBJECTIVE: To study the association between serum anti-Müllerian hormone (AMH) levels and follicular development and endocrine responses induced by increasing doses (5·2-12·1 μg/day) of a novel recombinant human FSH (rhFSH, FE 999049) in patients undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) in a GnRH antagonist protocol. DESIGN: Secondary analysis of a randomized controlled trial with stratified randomization according to AMH (lower stratum: 5·0-14·9 pmol/l; higher stratum: 15·0-44·9 pmol/l). PATIENTS: Infertile women of good prognosis (n = 265). MEASUREMENTS: Follicular development and endocrine parameters during controlled ovarian stimulation (COS) with rhFSH. RESULTS: Serum FSH levels increased with increasing rhFSH doses and steady-state levels for each dose were similar in both AMH strata. In the whole study population, significant (P < 0·001) positive dose responses were observed for the number of follicles ≥ 12 mm, and serum levels of oestradiol, inhibin B, inhibin A and progesterone at end of stimulation. In comparison with the higher AMH stratum, patients in the lower AMH stratum had significantly different slopes of the dose-response curves for these hormones, and no clear dose-related increase was observed for the number of follicles in these patients. CONCLUSIONS: Dose-response relationships between rhFSH and follicular development and endocrine parameters are significantly different for IVF/ICSI patients with lower and higher serum AMH levels at start of COS.
- MeSH
- Anti-Mullerian Hormone blood MeSH
- Adult MeSH
- Fertilization in Vitro MeSH
- Follicle Stimulating Hormone blood therapeutic use MeSH
- Ovulation Induction methods MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Pregnancy MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
OBJECTIVE: To evaluate the dose-response relationship of a novel recombinant human FSH (rhFSH; FE 999049) with respect to ovarian response in patients undergoing IVF/intracytoplasmic sperm injection treatment; and prospectively study the influence of initial antimüllerian hormone (AMH) concentrations. DESIGN: Randomized, controlled, assessor-blinded, AMH-stratified (low: 5.0-14.9 pmol/L [0.7-<2.1 ng/mL]; high: 15.0-44.9 pmol/L [2.1-6.3 ng/mL]) trial. SETTING: Seven infertility centers in four countries. PATIENT(S): Two hundred sixty-five women aged ≤37 years. INTERVENTION(S): Controlled ovarian stimulation with either 5.2, 6.9, 8.6, 10.3, or 12.1 μg of rhFSH, or 11 μg (150 IU) of follitropin alfa in a GnRH antagonist cycle. MAIN OUTCOME MEASURE(S): Number of oocytes retrieved. RESULT(S): The number of oocytes retrieved increased in an rhFSH dose-dependent manner, from 5.2 ± 3.3 oocytes with 5.2 μg/d to 12.2 ± 5.9 with 12.1 μg/d. The slopes of the rhFSH dose-response curves differed significantly between the two AMH strata, demonstrating that a 10% increase in dose resulted in 0.5 (95% confidence interval 0.2-0.7) and 1.0 (95% confidence interval 0.7-1.3) more oocytes in the low and high AMH stratum, respectively. Fertilization rate and blastocyst/oocyte ratio decreased significantly with increasing rhFSH doses in both AMH strata. No linear relationship was observed between rhFSH dose and number of blastocysts overall or by AMH strata. Five cases of ovarian hyperstimulation syndrome were reported for the three highest rhFSH doses and in the high AMH stratum. CONCLUSION(S): Increasing rhFSH doses results in a linear increase in number of oocytes retrieved in an AMH-dependent manner. The availability of blastocysts is less influenced by the rhFSH dose and AMH level. CLINICAL TRIAL REGISTRATION NUMBER: NCT01426386.
- MeSH
- Anti-Mullerian Hormone administration & dosage MeSH
- Adult MeSH
- Fertilization in Vitro methods MeSH
- Follicle Stimulating Hormone, Human administration & dosage MeSH
- Ovulation Induction methods MeSH
- Sperm Injections, Intracytoplasmic methods MeSH
- Humans MeSH
- Oocyte Retrieval * MeSH
- Recombinant Proteins administration & dosage MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase II MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
- MeSH
- Infertility classification therapy MeSH
- Follow-Up Studies MeSH
- Preimplantation Diagnosis methods adverse effects MeSH
- Age Factors MeSH
- Publication type
- Abstracts MeSH
