Open Access Protocol BMJ Open: first published as 10.1136/bmjopen-2013-002938 on 1 June 2013. Downloaded from Corifollitropin α followed by menotropin for poor ovarian responders’ trial (COMPORT): a protocol of a multicentre randomised trial Nikolaos P Polyzos,1 Michel Camus,1 Joaquin Llacer,2 Konstantinos Pantos,3 Herman Tournaye1 To cite: Polyzos NP, ABSTRACT ARTICLE SUMMARY Camus M, Llacer J, et al. Background: Poor response to ovarian stimulation α Corifollitropin followed by affects a significant proportion of infertile couples menotropin for poor ovarian Article focus undergoing in vitro fertilisation (IVF) treatment. responders’ trial (COMPORT): ▪ Recently, the European Society of Human a protocol of a multicentre Recently, the European Society of Human Reproduction and Embryology (ESHRE) devel- randomised trial. BMJ Open Reproduction and Embryology developed new criteria oped new criteria to define women with poor 2013;3:e002938. to define poor ovarian response, the so-called ovarian response after ovarian stimulation for in doi:10.1136/bmjopen-2013- Bologna criteria. Although preliminary studies in vitro fertilisation (IVF), ‘The Bologna criteria’. 002938 these patients demonstrated very low pregnancy ▪ Up to date no randomised trial has been pub- rates, a recent pilot study has shown promising lished to evaluate the effectiveness of ovarian ▸ Prepublication history for results in women <40 years old fulfilling the criteria, stimulation protocols in poor ovarian responders this paper is available online. after treatment with corifollitropin α followed by according to the new ESHRE definition. To view these files please highly purified menotropin (hpHMG) in a ▪ Although poor ovarian responders according to visit the journal online gonadotropin-releasing hormone (GnRH) antagonist the Bologna criteria have very low pregnancy (http://dx.doi.org/10.1136/ setting. Corifollitropin α followed by menotropin for rates after ovarian stimulation for IVF, recently a http://bmjopen.bmj.com/ bmjopen-2013-002938). poor ovarian responders’ trial (COMPORT) is a pilot study demonstrated that corifollitropin α randomised trial aiming to investigate whether this followed by highly purified menotropin (hpHMG) Received 23 March 2013 novel protocol is superior to treatment with may result in very promising pregnancy rates. Revised 17 April 2013 Accepted 3 May 2013 recombinant follicle-stimulating hormone (FSH) in an antagonist setting for young poor Key messages ▪ α responders. Corifollitropin followed by menotropin for poor ovarian responders’ trial will provide conclusive This final article is available Methods/design: COMPORT is a multicentre, open evidence regarding the superiority of a novel for use under the terms of label, phase III randomised trial using a parallel two- protocol with corifollitropin α followed by the Creative Commons arm design. 150 patients <40 years old fulfilling the on October 1, 2021 by guest. Protected copyright. hpHMG versus recombinant follicle-stimulating Attribution Non-Commercial ‘Bologna criteria’ will be randomised to corifollitropin hormone in a gonadotropin-releasing hormone 2.0 Licence; see α followed by hpHMG (group A) or recombinant FSH http://bmjopen.bmj.com antagonist setting for the treatment of young (group B) in a GnRH antagonist protocol for (<40 years old) poor ovarian responders accord- IVF/intracytoplasmic sperm injection (ICSI). The ing to the Bologna criteria. primary outcome is the ongoing pregnancy rate (defined as the presence of intrauterine gestational Strengths and limitations of this study 1 Centre for Reproductive sac with an embryonic pole demonstrating cardiac ▪ This is the first randomised study to examine the Medicine, Universitair activity at 9–10 weeks of gestation). Secondary efficacy of two stimulation protocols in poor Ziekenhuis Brussel, Vrije outcomes are clinical and biochemical pregnancy ovarian responders as described by the newly Universiteit Brussel, Brussels, rates and number of oocytes retrieved. Central developed ESHRE definition. Belgium randomisation will be performed using a computer- ▪ To ensure sufficient power, the study’s sample 2Instituto Bernabeu, Alicante, Spain generated list and allocation concealment will be size calculation was based on a previous pilot α 3Genesis Athens, Athens, secured with the use of sealed-opaque envelopes. study with the use of corifollitropin followed Greece A sample size of 150 women is essential to detect a by hpHMG in the antagonist setting. A sample difference of 19.5% in ongoing pregnancy rates size of 150 patients has 85% power to detect Corresponding to between group A (28%) and group B (8.5%) with a significant differences. Dr Nikolaos P Polyzos; power of 85% and a level of significance at 0.05 ▪ The study is focusing only in young poor [email protected], using a two-sided Fisher’s exact test. responders (<40 years). Women of advanced age nikolaos.polyzos@uzbrussel. (≥40 years) were not included in the study. be Polyzos NP, Camus M, Llacer J, et al. BMJ Open 2013;3:e002938. doi:10.1136/bmjopen-2013-002938 1 Corifollitropin α followed by menotropin for poor ovarian responders’ trial BMJ Open: first published as 10.1136/bmjopen-2013-002938 on 1 June 2013. Downloaded from INTRODUCTION demonstrated an ongoing pregnancy rate of 28% in According to the Human Fertilisation and Embryology women <40 years, strongly suggesting the conduction of Authority, live-birth rate per started cycle after in vitro a future randomised trial testing this novel treatment fertilisation (IVF) has increased fairly consistently from protocol.10 14% in 1991 to 24.5% in 2010.1 Nonetheless, despite this substantial increase in live-birth rates over the years, specific patient populations experience low-pregnancy SUMMARY: RATIONALE FOR COMPORT STUDY ‘ ’ rates due to their limited ovarian response after ovarian The recently developed Bologna criteria by The stimulation for IVF.2 Poor ovarian responders are women ESHRE working group on Poor Ovarian Response fi fi who fail to respond to ovarian stimulation treatment and De nition represent the rst realistic attempt by a scien- fi fi represent up to 20% of the population seeking fertility ti c community (ESHRE) to standardise the de nition advice.3 of poor ovarian response in a simple and reproducible Despite the numerous trials conducted in women with manner, and randomised trials are needed to test the poor ovarian response, pregnancy rates remain low, with pregnancy rates in this population. In combination with studies reporting a live-birth of less than 10% irrespect- the existing literature, our previous work indicates that fi ive of the treatment protocol used and the age of the (1) women ful lling these criteria have very low preg- patients.45Yet, a considerable limitation of all the ran- nancy rates, irrespective of age (2) current treatment domised trials up to date is the lack of a uniform defin- protocols demonstrate ongoing pregnancy rates that do α ition to describe poor ovarian responders. Up to 2011, not exceed 8.5% and (3) corifollitropin followed by among 47 randomised trials in women with poor hpHMG might increase ongoing pregnancy rates in fi ovarian response, 41 different definitions for poor young patients (<40 years old) ful lling the criteria. fi fi ovarian response were utilized6; surprisingly, no more These ndings provide a strong rationale for a de nitive α than three trials used the same definition, whereas even large randomised controlled trial. The corifollitropin ’ trials from the same group of investigators used different followed by menotropin for poor ovarian responders definitions among different trials.6 Thus, it appears that trial (COMPORT) study will provide conclusive evidence any effort to identify the most optimal treatment for regarding the superiority or not of this novel protocol α these women seems to be futile, simply due to the lack with corifollitropin followed by hpHMG for the treat- fi of a uniform definition to describe women failing to ment of young poor ovarian responders ful lling the respond to stimulation. Bologna criteria. Recently, the European Society of Human Reproduction and Embryology (ESHRE) developed a METHODS AND ANALYSIS new definition in order to select patients suitable for http://bmjopen.bmj.com/ Study design inclusion in future clinical trials as poor ovarian respon- The COMPORT is a multicentre, open label, phase III ders, the so-called Bologna criteria.7 However, a limited multicentre superiority randomised trial using a parallel number of studies has been published to date including group, two-arm design with 1:1 allocation ratio with a patients with poor ovarian response according to the primary endpoint ongoing pregnancy rates. Four partici- ‘Bologna criteria’, whereas no randomised trial is pub- pating centres in Europe will recruit women less than lished or ongoing for this population. 40 years who fulfil the Bologna criteria for poor ovarian Preliminary reports in ‘Bologna poor responders’ response. The COMPORT study will compare controlled highlight the limited prospects for these women. on October 1, 2021 by guest. Protected copyright. ovarian hyperstimulation for intracytoplasmic sperm injec- Natural cycle IVF has been shown to result in disap- tion (ICSI) with corifollitropin α followed by hpHMG pointingly low live-birth rates, regardless of patients’ versus recombinant follicle-stimulating hormone (rFSH), age8; ovarian stimulation with widely accepted treatment in a gonadotropin-releasing hormone antagonist setting. modalities,