Is there a place for corifollitropin alfa in IVF/ICSI cycles? A systematic review and meta-analysis

29 02 2012

To the Editor:

As the sponsor of all four trials included in a recent systematic review and meta-analysis of corifollitropin alfa, we reviewed the manuscript authored by Youssef and co-workers (1) with great interest. This combined analysis includes two phase II dose-finding trials and two phase III randomized controlled trials.

Related to the OHSS incidence per woman randomized, the authors report on page 3 that the number needed to harm (NNH) is equal to 1. This is an obvious error. If the absolute risk increase is 1% as the authors state, the NNH should have been 100. However, the absolute risk increase is less than 1%. This can be demonstrated by combining the control OHSS rate of 2% (page 3) with the OHSS odds ratio of 1.29 (figure 2C). This gives an Elonva OHSS rate of 2.6%, an increase of 0.6% corresponding to an NNH of 177. In a recent pooled analysis by Tarlatzis (2), only the two phase III randomized controlled trials were included and the odds ratio for OHSS, adjusted for trial, was 1.18 (95%CI 0.81-1.71).

It is the view of the sponsor that the inclusion of the two phase II dose-finding trials in this meta-analysis is incorrect, although exclusion of these smaller trials would not greatly alter its outcome. Nevertheless, the reader should understand that these trials clearly demonstrated that certain dosages of corifollitropin alfa were too low (60 µg), whereas other dosages (180 µg and 240 µg) were too high to support the first 7 days of ovarian stimulation (3,4). Final dose selection for phase III studies did take into account the clear inverse relationship between body weight and drug exposure. This resulted in the selection of 100 µg corifollitropin alfa for patients weighing ≤ 60 kg and of 150 µg of corifollitropin alfa weighing > 60 kg (5,6). Thus to evaluate the efficacy and safety of corifollitropin alfa in comparison to daily FSH, only data of randomized controlled phase III trials with the selected and registered doses of 100 and 150 µg corifollitropin alfa in the respective body weight groups should be combined.

To date, only two controlled phase III trials (7,8) have been published. Another large randomized clinical trial ( NCT01144416) (9) using the selected doses of corifollitropin alfa is underway and a combined analysis of the three phase III trials may be very helpful in the near future to further document potential differences between corifollitropin alfa and daily rFSH, which was used as a reference in all three phase III trials. We further suggest that combined analyses should preferably be performed using individual patient data rather than summary statistics of published manuscripts.

Bernadette Mannaerts, M.Sc., Global Clinical Research, MSD, Oss The Netherlands
Pierre Verweij, Ph.D., Biostatistics and Research Decision Sciences, MSD, Oss The Netherlands
Keith Gordon, Ph.D., Global Medical Affairs, Merck Sharp & Dohme Corp., Whitehouse Station, New Jersey USA


1. Youssef MAM, van Wely M, Aboulfoutouh I, El-Khyat W, van der Veen F, Al-Inany H, 2012. Is there a place for corifollitropin alfa in IVF/ICSI cycles? A systematic review and meta-analysis. Fertil Steril 2012; Article in Press.

2. Tarlatzis BC, Griesinger G, Leader A, Rombouts L, Ijzerman-boon PC, Mannaerts BMJL . Comparative incidence of ovarian hyperstimulation syndrome following ovarian stimulation with corifollitropin alfa or recombinant FSH. Reprod Biomed Online. 2012; Article in Press.

3. 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 fertilization. J Clin Endocrinol Metab 2004;89:2062–70.

4. 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;23:2484–92.

5. De Greef R, Zandvliet AS, de Haan AF, Ijzerman-Boon PC, Marintcheva-Petrova M, Mannaerts BM. Dose selection of corifollitropin alfa by modeling and simulation in controlled ovarian stimulation. Clin Pharmacol Ther 2010;88:79–87.

6. Ledger WL, Fauser BC, Devroey P, Zandvliet AS, Mannaerts BMJL Corifollitropin alfa doses based on body weight: clinical overview of drug exposure and ovarian response. Reprod Biomed Online 2011;23:150-9.

7. Devroey P, Boostanfar R, Koper NP, Mannaerts BM, Ijzerman-Boon PC, Fauser BC, ENGAGE Investigators. 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. Hum Reprod 2009;24:3063–72.

8. Corifollitropin Alfa Ensure Study Group. Corifollitropin alfa for ovarian stimulation in IVF: a randomized trial in lower-body-weight women. Reprod Biomed Online 2010;21:66-76.

9. NCT01144416. Efficacy and Safety Study of a Single Injection of SCH 900962 Versus Daily recFSH Injections in Women Undergoing Controlled Ovarian Stimulation (Study P06029) (PURSUE).

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.12.053

The authors respond:

We read the letter by Mannaerts et al. on our meta-analysis on corifollitropin alpha with interest. We welcome this opportunity to apologize for the typing error on NNT. The correct NNT is indeed almost 100.

The issue they raise on phase II versus phase III studies is an important one, but their interpretation of its significance is overlooking the role of the patient profile, like female age, ovarian reserve, duration of subfertility, etc. From this perspective we wholeheartedly support their suggestion to perform IPD meta-analyses to better define the proper place for corifollitropin alfa.

Mohamed Abdelfattah Mahmoud Youssef, M.D.,a,b,c Madelon van Wely, M.D.,b Ismail Aboulfoutouh, M.D.,c
Walid El-Khyat, M.D.,a Fulco van der Veen, Ph.D.,b and Hesham Al-Inany, Ph.D.a
a Department of Obstetrics and Gynaecology, Center for Reproductive Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
b Department of Obstetrics and Gynaecology, Center for Reproductive Medicine, Academic Medical Center, Amsterdam, the Netherlands
c Egyptian International Fertility Center–IVF, Cairo, Egypt

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.12.053




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