The current ENGAGE trial was a double-blind, double-dummy trial initiated to investigate whether the new corifollitropin alfa regimen provides similar success rates compared with the current care. The double-dummy approach guaranteed the blinding of medication during the trial and prevented any bias in terms of treatment decisions. Owing to the fact that the trial was powered to enable comparison of the ongoing pregnancy rates as the primary study end-point, this is the largest double-blind efficacy trial in IVF performed to date. The outcome of the trial provides compelling evidence of equal efficacy in terms of ongoing pregnancy rates, because the point estimates i.e. 38.9 and 38.1% for the ongoing pregnancy rates were very close for the two treatment groups and the 95% lower limit of the difference was only −3.9%. Subset analyses of subjects undergoing IVF or ICSI and of subjects who had single or double embryo transfer reveal consistently high ongoing pregnancy rates, similar between the treatment groups, which confirm the robustness of the primary end-point. Even though an equal number and quality of embryos were replaced in both treatment groups, the multiple pregnancy rate in the corifollitropin alfa group tended to be higher (+4.4% absolute risk increase) than in the reference group, which may be related to the slightly higher implantation rate. This increase, although not significant, cannot be ruled out and may prove to be clinically relevant, given the low power of the study to detect such a difference (c.22%). In this context, it should be emphasized that both treatment arms used a ‘protocolized’ fixed dose treatment regimen applying GnRH antagonist (ganirelix) co-treatment, which confirms the successful outcome of a patient-friendly short GnRH antagonist protocol in corifollitropin alfa, as well as rFSH, treatment cycles. In addition, one-third of the patients treated with a single injection of corifollitropin alfa reached the criteria for hCG injection prior to or on stimulation day 8, omitting the need for any additional FSH injections. The ongoing pregnancy rate of this subset of good responder patients was 44.0%, thus 5.9% higher than the overall group of subjects treated with corifollitropin alfa.
A hybrid molecule composed of human FSH and the CTP of hCG was first described by Boime and colleagues (Fares et al., 1992
). In subsequent clinical trials the new recombinant fertility hormone exhibited a slower absorption (and subsequent rise to peak levels) and an approximately 2-fold longer t1/2
compared with rFSH (Bouloux et al., 2001
; Duijkers et al., 2002
). After corifollitropin alfa injection, peak levels of FSH activity are reached within 2 days whereas steady state levels with daily FSH are reached only after 4–5 days (Mannaerts et al., 1996
). These pharmacokinetic properties of corifollitropin alfa create an opportunity to further simplify ovarian stimulation protocols for IVF by omitting the need for daily gonadotrophin injections during the first week of stimulation (Fauser et al., 2009
). In the current trial, the difference in exposure during the first days of stimulation may have resulted in a slightly higher ovarian response in the corifollitropin alfa treated patients, as previous trials with rFSH have shown that the number of follicles recruited increases with the starting dose of rFSH given (Wikland et al., 2001
; Out et al., 2004
). In view of the equal pregnancy rates, the current trial does not suggest that the higher exposure to FSH immunoactivity during the first days of stimulation interferes with the endometrial receptivity.
In this trial hormonal pretreatment with oral contraceptives or supplementation with LH or hCG during the treatment phase was not allowed per protocol. The efficacy results in this large, global, multi-center trial suggest that the amount of endogenous LH during treatment with either corifollitropin alfa or daily rFSH in a standard GnRH antagonist protocol is sufficient to support high success rates in terms of ongoing pregnancies (Cedrin et al., 2004
Because of concerns that the relatively high exposure to corifollitropin alfa during the first days of stimulation might initiate an early rise of LH (Devroey et al., 2004
), all patients in this trial started treatment with ganirelix on stimulation day 5. This fixed start of GnRH antagonist co-treatment was considered advantageous from an efficacy perspective as this may result in higher pregnancy rates, as well as from a methodological point of view as this reduces variability in the applied treatment regimens (Kolibianakis et al., 2004
; Al-Inany et al., 2005
; Arce et al., 2005
The corifollitropin alfa regimen used in this trial comprised a single dose of corifollitropin alfa followed by daily doses of rFSH (as needed up to a daily maximum of 200 IU). This corifollitropin regimen was compared with a fixed dose of 200 IU/day rFSH for the first 7 days, but with the option to decrease the daily FSH dose in cases when hyper-response was observed. Thus there was a difference in patient management options, with no option to adjust the dosing during the first week of stimulation in the corifollitropin arm. After corifollitropin alfa injection, serum FSH activity declines from stimulation day 3 (Cmax) onwards, but further reduction of exposure during the first week of stimulation cannot be attained.
The validity of the claimed efficacy and safety data of this trial are limited to the study population only. Patients with known risk factors for a hyper-response, such as patients with a history of OHSS, with PCOS or with a high AFC (>20) were excluded from the current trial. In addition, patients with a history of low ovarian response in a previous IVF cycle were excluded. However, it should be noted that 74% of the patients included in this trial underwent their first IVF cycle for which the ovarian response is less predictable and will still include low- and high responder patients.
In this large cohort of (potential) normal responder patients, corifollitropin alfa has been shown to be well tolerated and non-immunogenic. In line with the higher ovarian response, the observed incidence of OHSS was higher in the corifollitropin alfa group, but the difference was not significant. Our study was not sufficiently powered to detect an underlying difference in the incidence of OHSS, and therefore its actual presence cannot be excluded. In line with the recruitment of slightly more follicles by corifollitropin alfa, dose reductions during stimulation were more frequently made in the corifollitropin alfa group than in the reference group. Clearly, a minority of subjects required a dose reduction on stimulation day 6 or 7, which may have affected the ovarian response in the rFSH group rather than in the corifollitropin alfa group in which only the placebo was reduced.
Appropriate clinical monitoring and lowering or withholding the daily rFSH dose to complete the cycle, as well as lowering or withholding the dose of hCG to trigger final oocyte maturation, or cryopreservation of all embryos obtained are options which can be considered as part of patient management to minimize the risk of OHSS (Delvigne and Rozenberg, 2002
Owing to the double-blind design of the trial, requiring all patients to be treated with an equal number of injections, no comparative data could be collected on perceived patient convenience or preference for the corifollitropin alfa regimen. Since a single injection of corifollitropin alfa replaces the first seven daily injections of rFSH during ovarian stimulation, the intuitive advantages of such a simpler treatment regimen are obvious, but need to be confirmed in clinical practice. In addition to patient preference, future controlled trials may examine the efficacy of corifollitropin alfa in (potential) poor responding patients as well as the safety in (potential) high responders.
In conclusion, in this study we tested the efficacy (in terms of ongoing pregnancy rates) of substituting the first 7 daily doses of rFSH with a single injection of corifollitropin alfa in women undergoing ovarian stimulation for IVF/ICSI using rFSH and GnRH antagonists. Our data demonstrate that a single corifollitropin alfa injection results in an ongoing pregnancy rate which is equal to that of a daily rFSH regimen. Combined with appropriate patient selection and state-of-the-art clinical management during the stimulation phase of the treatment cycle, corifollitropin alfa potentially offers an attractive new treatment option for patients undergoing ovarian stimulation during ART.