A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol

P Devroey, R Boostanfar, N P Koper, B M J L Mannaerts, P C Ijzerman-Boon, B C J M Fauser, ENGAGE Investigators, Devroey, Dhont, Leader, Mardesic, Mrázek, Blaabjerg, Tapanainen, Varila, Barrière, Hedon, Fauser, Sterrenburg, Kahn, Von Düring, Bajo Arenas, Barri, Fernández-Sánchez, Bergh, Hillensjö, Balen, Ledger, Matthews, Abuzeid, Alper, Boostanfar, Doody, Frattarelli, Grunfeld, Karande, Kort, Levy, Lifchez, Pang, Schoolcraft, Yeko, P Devroey, R Boostanfar, N P Koper, B M J L Mannaerts, P C Ijzerman-Boon, B C J M Fauser, ENGAGE Investigators, Devroey, Dhont, Leader, Mardesic, Mrázek, Blaabjerg, Tapanainen, Varila, Barrière, Hedon, Fauser, Sterrenburg, Kahn, Von Düring, Bajo Arenas, Barri, Fernández-Sánchez, Bergh, Hillensjö, Balen, Ledger, Matthews, Abuzeid, Alper, Boostanfar, Doody, Frattarelli, Grunfeld, Karande, Kort, Levy, Lifchez, Pang, Schoolcraft, Yeko

Abstract

Background: Corifollitropin alfa, a fusion protein lacking LH activity, has a longer elimination half-life and extended time to peak levels than recombinant FSH (rFSH). A single injection of corifollitropin alfa may replace seven daily gonadotrophin injections during the first week of ovarian stimulation.

Methods: In this large, double-blind, randomized, non-inferiority trial the ongoing pregnancy rates were assessed after one injection of 150 microg corifollitropin alfa during the first week of stimulation and compared with daily injections of 200 IU rFSH using a standard GnRH antagonist protocol.

Results: The study population comprised 1506 treated patients with mean age of 31.5 years and body weight of 68.6 kg. Ongoing pregnancy rates of 38.9% for the corifollitropin alfa group and 38.1% for rFSH were achieved, with an estimated non-significant difference of 0.9% [95% confidence interval (CI): -3.9; 5.7] in favor of corifollitropin alfa. Stratified analyses of pregnancy rates confirmed robustness of this primary outcome by showing similar results regardless of IVF or ICSI, or number of embryos transferred. A slightly higher follicular response with corifollitropin alfa resulted in a higher number of cumulus-oocyte-complexes compared with rFSH [estimated difference 1.2 (95% CI: 0.5; 1.9)], whereas median duration of stimulation was equal (9 days) and incidence of (moderate/severe) ovarian hyperstimulation syndrome was the same (4.1 and 2.7%, respectively P = 0.15).

Conclusion: Corifollitropin alfa is a novel and effective treatment option for potential normal responder patients undergoing ovarian stimulation with GnRH antagonist co-treatment for IVF resulting in a high ongoing pregnancy rate, equal to that achieved with daily rFSH. The trial was registered under ClinicalTrials.gov identifier NTC00696800.

Trial registration: ClinicalTrials.gov NCT00696800.

Figures

Figure 1
Figure 1
Graphical illustration of the treatment regimens applied in this trial. Upper panel depicts investigational group (corifollitropin alfa), lower panel depicts reference group (rFSH). rFSH: recombinant FSH, P: progesterone.
Figure 2
Figure 2
Flow chart showing the number of participants at each stage of the clinical trial.
Figure 3
Figure 3
Ongoing pregnancy rates stratified for fertilization procedure, number of embryos transferred and day of transfer. Subset with double embryo transfer includes three patients with three embryos transferred.

References

    1. Al-Inany H, Aboulghar MA, Mansour RT, Serour GI. Optimizing GnRH antagonist administration: meta-analysis of fixed versus flexible protocol. Reprod Biomed Online. 2005;10:567–570.
    1. Arce JC, Nyboe Andersen A, Collins J. Resolving methodological and clinical issues in the design of efficacy trials in assisted reproductive technologies: a mini-review. Hum Reprod. 2005;20:1757–1771.
    1. Boivin J, Takefman JE. Impact of the in-vitro fertilization process on emotional, physical and relational variables. Hum Reprod. 1996;11:903–907.
    1. Bouloux PM, Handelsman DJ, Jockenhövel F, Nieschlag E, Rabinovici J, Frasa WL, de Bie JJ, Voortman G, Itskovitz-Eldor J FSH-CTP study group. First human exposure to FSH-CTP in hypogonadotrophic hypogonadal males. Hum Reprod. 2001;16:1592–1597.
    1. Cédrin-Durnerin I, Grange-Dujardin D, Laffy A, Parneix I, Massin N, Galey J, Théron L, Wolf JP, Conord C, Clément P, et al. Recombinant human LH supplementation during GnRH antagonist administration in IVF/ICSI cycles: a prospective randomized study. Hum Reprod. 2004;19:1979–1984.
    1. Cousineau TM, Domar AD. Psychological impact of infertility. Best Pract Res Clin Obstet Gynaecol. 2007;21:293–308.
    1. De Greef R, Struijs M, de Haan A, Marintcheva-Petrova M, Mannaerts BMJL. Dose selection of Org 36286 (corifollitropin alfa) using pharmacokinetic and dynamic modeling and simulation. Hum Reprod. 2007;22:i39. (Abstract O-099)
    1. Delvigne A, Rozenberg S. Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review. Hum Reprod Update. 2002;8:559–577.
    1. Devroey P, Fauser BC, Platteau P, Beckers NG, Dhont M, Mannaerts BM. Induction of multiple follicular development by a single dose of long-acting recombinant follicle-stimulating hormone (FSH-CTP, corifollitropin alfa) for controlled ovarian stimulation before in vitro fertilisation. J Clin Endocrinol Metab. 2004;89:2062–2070.
    1. Domar AD, Zuttermeister PC, Friedman R. Psychological impact of infertility: a comparison with patients with other medical conditions. J Psychosom Obstet Gynaecol. 1993;14:45–52.
    1. Duijkers IJM, Klipping C, Boerrigter PJ, Machielsen CSM, de Bie JJ, Voortman G. Single dose pharmacokinetics and effects on follicular growth and serum hormones of a long-acting recombinant FSH preparation (FSH-CTP) in healthy pituitary-suppressed females. Hum Reprod. 2002;17:1987–1993.
    1. Fares FA, Suganuma N, Nishimori K, LaPolt PS, Hsueh AJ, Boime I. Design of a long-acting follitropin agonist by fusing the C-terminal sequence of the chorionic gonadotropin beta subunit to the follitropin beta subunit. Proc Natl Acad Sci USA. 1992;89:4304–4308.
    1. Fauser BCJM, Mannaerts BMJL, Devroey P, Leader A, Boime I, Baird DT. Advances in recombinant DNA technology: corifollitropin alfa, a hybrid molecule with sustained follicle-stimulating activity and reduced injection frequency. Hum Reprod Update. 2009 (E Pub Ahead of Print)
    1. Gleicher N, Weghofer A, Barad D. A formal comparison of the practice of assisted reproductive technologies between Europe and the USA. Hum Reprod. 2006;21:1945–1950.
    1. Gleicher N, Weghofer A, Barad D. Update on the comparison of assisted reproduction outcomes between Europe and the USA: the 2002 data. Fertil Steril. 2007;87:1301–1305.
    1. Hammarberg K, Astbury J, Baker HWG. Women's experience of IVF: a follow-up study. Hum Reprod. 2001;16:374–383.
    1. Heijnen EM, Macklon NS, Fauser BCJM. What is the most relevant standard of success in assisted reproduction? The next step to improving outcomes of IVF: consider the whole treatment. Hum Reprod. 2004;19:1936–1938.
    1. Kolibianakis EM, Zikopoulos K, Schiettecatte J, Smitz J, Tournaye H, Camus M, Van Steirteghem AC, Devroey P. Profound LH suppression after GnRH antagonist administration is associated with a significantly higher ongoing pregnancy rate in IVF. Hum Reprod. 2004;19:2490–2496.
    1. Land JA, Courtar DA, Evers JLH. Patient dropout in an assisted reproductive technology program: implications for pregnancy rates. Fertil Steril. 1997;68:278–281.
    1. LaPolt PS, Nishimori K, Fares FA, Perlas E, Boime I, Hsueh AJ. Enhanced stimulation of follicle maturation and ovulatory potential by long acting follicle-stimulating hormone agonists with extended carboxyl-terminal peptides. Endocrinology. 1992;131:2514–2520.
    1. Mannaerts BMJL, Shoham Z, Schoot D, Bouchard P, Harlin J, Fauser BCJM, Jacobs H, Rombout F, Coelingh Bennik H. Single-dose pharmacokinetics and pharmacodynamics of recombinant human follicle-stimulating hormone (Org 32849) in gonadotropin-deficient volunteers. Fertil Steril. 1993;59:108–114.
    1. Mannaerts BMJL, Rombout F, Out HJ, Coelingh Bennink HJT. Clinical profiling of recombinant follicle stimulating hormone (rFSH; Puregon): relationship between serum FSH and efficacy. Hum Reprod Update. 1996;2:153–161.
    1. Olivennes F. Patient-friendly ovarian stimulation. Reprod Biomed Online. 2003;7:30–34.
    1. Olivius C, Friden B, Lundin K, Bergh C. Cumulative probability of live birth after three in vitro fertilization/intracytoplasmic sperm injection cycles. Fertil Steril. 2002;77:505–510.
    1. Olivius C, Friden B, Borg G, Bergh C. Why do couples discontinue in vitro fertilisation treatment? A cohort study. Fertil Steril. 2004;81:258–261.
    1. Out HJ, Rutherford A, Fleming R, Tay CC, Trew G, Ledger W, Cahill D. A randomized, double-blind, multicentre clinical trial comparing starting doses of 150-200 IU of recombinant FSH in women treated with the GnRH antagonist ganirelix for assisted reproduction. Hum Reprod. 2004;19:90–95.
    1. Papanikolaou EG, Pozzobon C, Kolibianakis EM, Camus M, Tournaye H, Fatemi HM, Van Steirteghem AC, Devroey P. Incidence and prediction of ovarian hyperstimulation syndrome in women undergoing gonadotropin-releasing hormone antagonist in vitro fertilization cycles. Fertil Steril. 2006;85:112–120.
    1. Pennings G, Ombelet W. Coming soon to your clinic: patient-friendly ART. Hum Reprod. 2007;22:2075–2079.
    1. Rajkhowa M, Mcconnell A, Thomas GE. Reasons for discontinuation of IVF treatment: a questionnaire study. Hum Reprod. 2006;21:358–363.
    1. Schröder AK, Katalinic A, Diedrich K, Ludwig M. Cumulative pregnancy rates and drop-out rates in a German IVF programme: 4102 cycles in 2130 patients. Reprod Biomed Online. 2004;8:600–606.
    1. Tarlatzis BC, Fauser BCJM, Kolibianakis EM, Diedrich K, Devroey P on behalf of the Brussels GnRH Antagonist Consensus Workshop Group. GnRH antagonists in ovarian stimulation for IVF. Hum Reprod Update. 2006;12:333–340.
    1. The Corifollitropin Alfa Dose-Finding Study Group. A randomized dose-response trial of a single injection of corifollitropin alfa to sustain multifollicular growth during controlled ovarian stimulation. Hum Reprod. 2008;23:2484–2492.
    1. Van der Gaast M, Eijkemans MJC, Van der Net JB, de Boer EJ, Burger CW, Van Leeuwen FE, Fauser BCJM, Macklon NS. Optimum number of oocytes for a successful first IVF treatment cycle. Reprod Biomed Online. 2006;13:476–480.
    1. Verberg MF, Eijkemans MJ, Heijnen EM, Broekmans FJ, de Klerk C, Fauser BCJM, Macklon NS. Why do couples drop out from IVF treatment? A prospective cohort study. Hum Reprod. 2008;23:2050–2055.
    1. Verwoerd GR, Mathews T, Brinsden PR. Optimal follicle and oocyte numbers for cryopreservation of all embryos in IVF cycles at risk of OHSS. Reprod Biomed Online. 2008;17:312–317.
    1. Wikland M, Bergh C, Borg K, Hillensjo T, Howles CM, Knutsson A, Nilsson L, Wood M. A prospective, randomized comparison of two starting doses of recombinant FSH in combination with cetrorelix in women undergoing ovarian stimulation for IVF/ICSI. Hum Reprod. 2001;16:1676–1681.
    1. WHO. Agents stimulating gonadal function in the human. World Health Organ Tech Rep Ser. 1973;514:1–30.

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