This study reports on a preplanned subgroup analysis in Chinese IVF/ICSI patients participating in the GRAPE study [16] which was adequately powered for the primary endpoint ongoing pregnancy. This study compared ovarian stimulation with individualized dosing of follitropin delta, based on pretreatment AMH concentrations and body weight, to follitropin alfa dosed according to label. Non-inferiority of follitropin delta compared to follitropin alfa was confirmed among women recruited from mainland China only, which was consistent with the overall population in the Pan-Asian study [16]. Moreover, the live birth rates of 31.0% for individualized dosing of follitropin delta and 25.5% for conventional dosing of follitropin alfa confirmed the favorable ongoing pregnancy rates in Chinese IVF/ICSI patients. In comparison to previous comparative trials of follitropin delta in European [1] and Japanese [15], Chinese patients were younger, with a lower body weight and higher serum AMH levels thus received in this study more frequently a lower dose of follitropin delta. The proportion of potential high responders (subjects with AMH ≥ 15 pmol/l) was almost 80% in the Chinese subgroup, whereas the corresponding numbers were 55% in the European trial and 59% in the Japanese trial. This, together with the lower body weight resulted in a lower mean follitropin delta dose administrated in this trial, namely 76.7 µg in Chinese patients compared to 90.0 µg in European and 83.5 µg in Japanese patients. Hence, the overall results in the Chinese population are closer to those of potential high responders in the European trial who required only 67.4 µg follitropin delta [19].
Overall, due to individualized dosing in the follitropin delta group, patients in this trial developed significantly fewer follicles at the end of stimulation with lower serum oestradiol, progesterone, inhibin A and inhibin B levels in the follitropin delta group than that in the follitropin alfa group. This overall lower ovarian response was mainly due to potential high responders (as indicated by serum AMH ≥ 15 pmol/L), who had a lower average oocyte yield i.e 10.5 for follitropin delta and 13.9 for follitropin alfa, indicating that stimulation with follitropin delta also normalizes ovarian response in Chinese high responders. In contrast, in potential low responders (as indicated by serum AMH < 15 pmol/L), more oocytes were retrieved in the follitropin delta group than in the follitropin alfa group (mean 9.2 vs 7.7). These results are in agreement with previous controlled trials of follitropin delta in Europe and Asia [1, 16] although in the current trial relatively more potential high responders were recruited. Regardless the population, there were no significant differences between groups in terms of percentage of women with embryo transfer, and the ongoing pregnancy rates were unaffected, indicating no difference in the quality of embryos transferred.
Thanks to the normalized ovarian response of potential high responders treated with follitropin delta, a lower incidence of early OHSS and/or incidence of preventive interventions was observed for women with follitopin delta compared to women treated with follitropin alfa. The improved safety outcome in this trial is in line with the analysis of the ESTHER-1 and ESTHER-2 study [20] showing a 50% reduction in incidence of moderate/severe OHSS with individualized follitropin delta compared with conventional dosing approach. For potential high responders, applying algorithm-based dosing of follitropin delta determines the dose of follitropin delta by incorporating a women’s serum AMH and body weight can mitigate the risk of OHSS due to ovarian stimulation. Although GnRH agonist triggering and freezing of all embryos lowers the risk of OHSS, patients have to wait until at least one more cycle for embryo transfer which delays their time to pregnancy [3].
The dose equivalence factor was assessed in this study to determine which dose of follitropin delta provides in Chinese women similar ovarian response as 150 IU of follitropin alfa. It was estimated that a daily follitropin delta dose of ≈10 µg would provide the same ovarian response as a starting dose of 150 IU/d of follitropin alfa (11 µg). This dose equivalence factor in Chinese women is consistent with the previous calculated factor for European and other western women [18] and confirms that one µg follitropin delta is more potent than one µg of follitropin alfa. Understanding the dose equivalence factor may help clinicians who are accustomed to IU doses to understand the anticipated ovarian response to different doses of follitropin delta and avoid dosing misunderstandings/errors.
In this trial the average total dose was 76.7 µg in the follitropin delta group and 1505 IU (110.4 µg) in the follitropin alfa group. Applying the dose equivalence factor, a follitropin delta dose of 76.7 µg was estimated to provide the same ovarian response as 1150.5 IU follitropin alfa. In this trial, the follitropin alfa dose was on average 354.5 IU more per patient than what was needed to get the same ovarian response as subjects treated with individualized follitropin delta. The difference in dose between the two groups was larger in the current study than in previous comparative studies, as the Chinese population included relatively more women with AMH ≥ 15 pmol/L and a lower body weight [1, 15].
China has the largest population in the world. Currently, ART services are not covered by any medical insurance system at national level. Although the development of ART in mainland China has presented a rapid growth, imbalance of ART service still exists geographically [21, 22]. In China, patients tend to seek public hospitals in the eastern big cities for ART service far away from their domestic region [23]. Overall, there is a need in China for patient-friendly and safer IVF treatment implying less complications and less visits to the clinic, which may be brought closer by individualized FSH dosing as reported in this trial.
Strengths and limitations
Advantages
This is the first efficacy and safety analysis of the individualized follitropin delta treatment compared to conventional follitropin alfa treatment in Chinese IVF patients. The data presented confirmed the benefits of follitropin delta dosing based on AMH and body weight, regardless ethnicity, resulting in a balanced efficacy and safety outcome with decreased risk of OHSS and reduced gonadotropin use.
Limitations
This study concerns a subgroup analysis of GRAPE study limited to Chinese patients, thus excluding patients outside mainland China. In addition, the live births were collected as follow-up data and the dose equivalence factor was a retrospective analysis. The cost-effectiveness of follitropin delta versus follitropin alfa in China should be further analyzed to provide guidance for clinicians and patients.