Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial

Individualized follitropin delta was similar to conventional follitropin alfa in ongoing pregnancy and ongoing implantation rates but gave more targeted response and fewer ovarian hyperstimulation syndrome preventive measures.

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Volume 107, Issue 2, Pages 387–396

Authors:

Anders Nyboe Andersen, M.D., Ph.D., Scott M. Nelson, M.R.C.O.G., Ph.D., Bart C.J.M. Fauser, M.D., Ph.D., Juan Antonio García-Velasco, M.D., Ph.D., Bjarke M. Klein, Ph.D., Joan-Carles Arce, M.D., Ph.D., the ESTHER-1 study group

Abstract:

Objective

To compare the efficacy and safety of follitropin delta, a new human recombinant FSH with individualized dosing based on serum antimüllerian hormone (AMH) and body weight, with conventional follitropin alfa dosing for ovarian stimulation in women undergoing IVF.

Design

Randomized, multicenter, assessor-blinded, noninferiority trial (ESTHER-1).

Setting

Reproductive medicine clinics.

Patient(s)

A total of 1,329 women (aged 18–40 years).

Intervention(s)

Follitropin delta (AMH <15 pmol/L: 12 μg/d; AMH ≥15 pmol/L: 0.10–0.19 μg/kg/d; maximum 12 μg/d), or follitropin alfa (150 IU/d for 5 days, potential subsequent dose adjustments; maximum 450 IU/d).

Main Outcomes Measure(s)

Ongoing pregnancy and ongoing implantation rates; noninferiority margins −8.0%.

Result(s)

Ongoing pregnancy (30.7% vs. 31.6%; difference −0.9% [95% confidence interval (CI) −5.9% to 4.1%]), ongoing implantation (35.2% vs. 35.8%; −0.6% [95% CI −6.1% to 4.8%]), and live birth (29.8% vs. 30.7%; −0.9% [95% CI −5.8% to 4.0%]) rates were similar for individualized follitropin delta and conventional follitropin alfa. Individualized follitropin delta resulted in more women with target response (8–14 oocytes) (43.3% vs. 38.4%), fewer poor responses (fewer than four oocytes in patients with AMH <15 pmol/L) (11.8% vs. 17.9%), fewer excessive responses (≥15 or ≥20 oocytes in patients with AMH ≥15 pmol/L) (27.9% vs. 35.1% and 10.1% vs. 15.6%, respectively), and fewer measures taken to prevent ovarian hyperstimulation syndrome (2.3% vs. 4.5%), despite similar oocyte yield (10.0 ± 5.6 vs. 10.4 ± 6.5) and similar blastocyst numbers (3.3 ± 2.8 vs. 3.5 ± 3.2), and less gonadotropin use (90.0 ± 25.3 vs. 103.7 ± 33.6 μg).

Conclusion(s)

Optimizing ovarian response in IVF by individualized dosing according to pretreatment patient characteristics results in similar efficacy and improved safety compared with conventional ovarian stimulation.

Clinical Trial Registration Number

NCT01956110.


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Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders. The journal publishes juried original scientific articles in clinical and laboratory research relevant to reproductive endocrinology, urology, andrology, physiology, immunology, genetics, contraception, and menopause. Fertility and Sterility® encourages and supports meaningful basic and clinical research, and facilitates and promotes excellence in professional education, in the field of reproductive medicine.

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Go to the profile of PROF DR THOMAS D'HOOGHE, MD, PhD

Salvatore Longobardi, MD, PhD, Senior Medical Director Global Medical Affairs Fertility, Merck, Darmstadt, Germany

Thomas D’Hooghe, MD, PhD, Vice-President and Head, Global Medical Affairs Fertility, Merck, Darmstadt and Professor Reproductive Medicine, Department of Development and Regeneration, Group Biomedical Sciences, KU Leuven (University of Leuven), Belgium

The relevance of randomized controlled trials (RCTs) has long been established. Such trials significantly contribute to improve our knowledge, answer questions, and definitely change the standards of care. Thus, great attention and scrutiny should be used when evaluating such studies in terms of design, statistics and results according to strict criteria and guidelines for designing, implementing, and reporting RCTs. In addition, the paucity of public funds in our field increases the importance of properly designed high quality RCTs sponsored by pharmaceutical companies.

Recently, Andersen NA et al (1) published the results of the ESTHER-1 trial (Evidence-based Stimulation Trial with human rFSH in Europe and Rest of world 1). The Authors concluded that “the present trial demonstrates that an individualized follitropin delta dosing is non inferior to conventional follitropin alfa with respect to ongoing pregnancy rate, ongoing implantation rate, and also live births, with a concomitant reduction in iatrogenic complications, including preventive interventions of OHSS”. This publication also reported that individualized follitropin delta resulted in more women with target response (8–14 oocytes) (43.3% vs. 38.4%), fewer poor responses (fewer than four oocytes in patients with AMH <15 pmol/L) (11.8% vs.17.9%), fewer excessive responses (>15 or >20 oocytes in patients with AMH >15pmol/L) (27.9% vs. 35.1% and 10.1%vs. 15.6%, respectively), and fewer measures taken to prevent ovarian hyperstimulation syndrome (2.3% vs. 4.5%), despite similar oocyte yield and similar blastocyst numbers, and less gonadotropin use (90.0 + 25.3 vs. 103.7 + 33.6 mg).

In our opinion, major limitations in study design do not support the claims made regarding non-inferiority for primary outcomes ongoing pregnancy and implantation rates, or superiority for other outcomes as listed above.

Firstly, a fair comparative assessment is impossible since patients in the follitropin delta arm and patients in the comparator arm receiving follitropin alpha were not subject to the same dosing regimens in the ESTHER-1 trial. Follitropin delta was used in an individualized dosing regimen based on body weight & anti-Müllerian hormone (AMH), whereas follitropin alfa with a fixed and inappropriate starting dose of 150IU and with dose adjustments as of day 6.It is well known that the starting dose is a very important determinant of the total number of oocytes retrieved (2), and that significant proportions of patients require different starting doses than 150 IU to reach optimal stimulation (3-6). This is the reason why the Summary of Product Characteristics (SmPC) for GONAL-f recommends a starting dose for follitropin alfa between 150 IU and 225 IU (7). However, in the ESTHER-1 trial, investigators were only allowed a follitropin alfa starting dose of 150 IU, preventing them from using the full range of follitropin alfa starting doses (150–225 IU) provided in its label. As a result of this design, patients with AMH <15 pmol/L received a higher starting dose of follitropin delta (12 μg) than those treated with follitropin alpha (11 μg contained in 150 IU of follitropin alpha) (7). On the contrary, the total gonadotropin dose received was significantly lower for follitropin delta (90.0 + 25.3 μg) than for follitropin alpha (103.7 + 33.6 μg, p<.001) in all patients.

Secondly, only patients in the follitropin delta arm (not those in the follitropin alpha arm) were allowed the benefit of using clinical markers (body weight) and biomarkers (AMH) for determination of the starting dose, whereas these markers are used worldwide in real clinical practice for determination of the starting dose, regardless of the type of gonadotrophin used (4). Claims of non-inferiority can only be made if both products were used in exactly the same way in both arms, requiring a design where either both products were individually dosed based on AMH levels and body weight, or both products were used with a fixed starting dose that could be modified based on ovarian response.

Thirdly, as described in the Rekovelle/follitropin delta Assessment Report of the Committee for Medicinal Products for Human Use of the European Medicines Agency in October 2016 document (www.ema.europa.eu/docs/en_GB/document_library/.../WC500220237.pdf) (8),
the overall non-inferiority for ongoing pregnancy claimed in the ESTHER-1 trial (1) can be explained by some heterogeneity of responses related to female age. Indeed, non-inferiority for ongoing pregnancy rate was driven by only 15% of the study population (aged 38 or older), and in fact non-inferiority was not demonstrated for women aged 37 years or less, who represented the large majority (85%!) of the ESTHER-1 trial participants (8). These women aged 37 years or less also represented a good prognosis ART population, especially taking into account the in- and exclusion criteria used (1) and likely included most of the 629 participants (mITT population) (8) with serum AMH levels of 15 pmol/l or more. They were expected to benefit most from AMH determined dose setting for follitropin delta but ended up with a lower ongoing pregnancy rate after ovarian stimulation with follitropin delta than after ovarian stimulation with follitropin alpha. We hypothesize that this observation can be explained by higher egg quality obtained after ovarian stimulation with follitropin alpha then after ovarian stimulation with follitropin delta. This hypothesis is supported by a trend towards higher fertilization rates (62% versus 53-56%) and higher blastocyst/oocyte ratios (35% versus 29-31%) after ovarian stimulation with follitropin alpha 11 microgram (equal to 150 IU) when compared to follitropin delta doses 8.6 microgram, 10.3 microgram and 12.1 microgram, regardless of serum AMH levels below and above 15 pmol/l, as published in the Phase II Rekovelle trial (9).

Fourthly, the study was only powered to demonstrate non-inferiority for the primary outcome of ongoing pregnancy and implantation rates, and any conclusion regarding differences in pre-specified (1) secondary outcomes (live birth rates, targeted ovarian response, extreme ovarian response, embryology data, proportion of women with early and late OHSS and/or preventive intervention for early OHSS) can only be considered to be hypothesis generating. Furthermore, the authors failed to differentiate which analyses were planned in the Statistical Analysis Plan and which analyses were performed posthoc. We hypothesize that all the following variables, that were not mentioned as primary/secondary outcome variables in the published paper (1) or on clinicaltrials.gov (10), were analyzed posthoc: number of oocytes retrieved, women with dose adjustments implemented, ovarian response stratified by AMH subdividing women with AMH <15 pmol/L (at risk of hypo-response) versus women with AMH >15 pmol/L (at risk of hyper response), proportion of women with blastocysts cryopreserved. Furthermore, authors need to report specifically, and separately for each category, the proportion of patients with “extreme responses” predefined as <4, >= 15 and >=20 oocytes recovered (now represented as an aggregate result in Table 3).

For the reasons mentioned above, the design of the ESTHER-1 trial does not allow to conclude non-inferiority for follitropin delta versus follitropin alpha regarding primary outcomes ongoing pregnancy and implantation rates, or to claim any superiority based on secondary outcome or posthoc analysis.


References

1. Andersen N.A., Nelson S.M., Fauser B., García-Velasco J.A., Klein B.M. and Arce JC, for the ESTHER-1 study group. Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 non inferiority trial Fertil Steril 2017;107:387-396.e4. doi: 10.1016/j.fertnstert.2016.10.033. Epub 2016 Nov 29.

2. La Marca A, Grisendi V, Spada E, Argento C, Milani S, Plebani M, Seracchioli R, Volpe A. Reference values in ovarian response to controlled ovarian stimulation throughout the reproductive period. Gynecol Endocrinol 2014; 30: 66-9.

3. Popovic-Todorovic, B, Loft A, Bredkjaeer H.E, Bangsbøll S, Nielsen I.K, Andersen A.N. A prospective randomized clinical trial comparing an individual dose of recombinant FSH based on predictive factors versus a ‘standard’ dose of 150 IU/day in standard’ patients undergoing IVF/ICSI treatment. Hum. Reprod 2003; 18, 2275–2282.

4. La Marca, A, Sunkara S.K. Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice. Hum. Reprod. Update 2014;20, 124–140.

5. Papaleo E, Zaffagnini S, Munaretto M, Vanni VS, Rebonato G, Grisendi V, Di Paola R, La Marca A. Clinical application of a nomogram based on age, serum FSH and AMH to select the FSH starting dose in IVF/ICSI cycles: a retrospective two-centres study European Journal of Obstetrics & Gynecology and Reproductive Biology 2016; 207; 94–99.

6. Allegra A, Marino A, Volpes A, Coffaro F, Scaglione P, Gullo S, La Marca A. randomized controlled trial investigating the use of a predictive nomogram for the selection of the FSH starting dose in IVF/ICSI cycles. RBMOn line 2017;34: 429-438. doi: 10.1016/j.rbmo.2017.01.012. Epub 2017 Jan 23.

7. www.ema.europa.eu/docs/en_GB/document_library/EPAR.../WC500023748.pdf

8. European Medicines Agency. Committee for Medicinal Products for Human Use. Rekovelle/follitropin alpha Assessment Report, 13th October 2016, EMA/11072/2017 (www.ema.europa.eu/docs/en_GB/document_library/.../WC500220237.pdf).

9. Arce JC, Andersen AN, Fernández-Sánchez M, Visnova H, Bosch E, García-Velasco JA, Barri P, de Sutter P, Klein BM, Fauser BC. Ovarian response to recombinant human follicle-stimulating hormone: a randomized, antimüllerian hormone-stratified, dose-response trial in women undergoing in vitro fertilization/intracytoplasmic sperm injection.Fertil Steril. 2014; 102:1633-40.

10. https://clinicaltrials.gov/ct2/show/record/NCT01956110

Go to the profile of Joan-Carles Arce
Joan-Carles Arce over 3 years ago

Joan-Carles Arce, MD, PhD, Chief Scientific Officer, Ferring US, Parsippany, USA.
Bjarke Mirner Klein, PhD, Director, Biometrics, Ferring Pharmaceuticals, Copenhagen, Denmark.

We thank the Global Medical Affairs executives at Merck (EMD Serono) for their interest in our trial. We strongly refute the claim that the trial does not provide evidence of non-inferiority with respect to the co-primary endpoints. As it is well-known to those involved in the development of new medicines, there are rigorous and highly regulated processes in place. The trial protocol was specifically designed and powered to demonstrate non-inferiority for ongoing pregnancy and implantation in discussion with regulatory authorities. The protocol was reviewed and approved by health authorities in 11 countries and independent ethics committees covering 37 clinics. Finally, the trial conduct and results have subsequently been inspected and assessed by the European Medicines Agency, leading to the approval of follitropin delta (REKOVELLE®) based on established non-inferiority. Ferring continues to incorporate innovative concepts and emerging technologies in clinical development programs with the purpose of providing recommendations in the product labellings of new gonadotropins on how to improve patient safety without compromising efficacy. We are grateful to the many investigators and health care professionals who collaborate with us in this scientific endeavor.

The Merck executives state that the starting dose of 150 IU follitropin alfa (GONAL-F) used in our trial is “inappropriate”. While the European Summary of Product Characteristics (SmPC) for GONAL-F mentions a starting dose range of 150-225 IU, there are other regions where Merck recommends 150 IU as the only starting dose in non-suppressed cycles, such as in the United States (1, 2, 3) and also Canada (4) where trial participants were included. We are therefore surprised given their own prescribing documentation that the Merck executives suggest that 150 IU is “inappropriate”. Further, one can hypothesize that higher starting doses of follitropin alfa up to 225 IU would have led to even greater differences in safety profile between the two treatment groups in a high-risk population, where the incidence of early moderate/severe OHSS and/or preventive interventions for early OHSS was 7.7% with follitropin delta and 26.7% with follitropin alfa at a starting dose of 150 IU (5).

We agree with the Merck executives that it is of benefit to use clinical markers (body weight) and biomarkers (AMH) for determination of the starting dose. The clinical development program for follitropin delta (REKOVELLE®) has prospectively incorporated these parameters as part of the evidence base gathered during phase 2, leading to the establishment of an individualized dosing regimen with documented efficacy and safety during phase 3. It is suggested that follitropin alfa should have also been dosed by AMH and body weight, but this is clearly not a viable option given the above prescribing information for follitropin alfa. The suggestion to have used both gonadotropins at a fixed starting dose is contradictory to the clinical objective of follitropin delta (REKOVELLE®) which is individualized dosing, and the view point that new innovative treatment modalities should be forced into the old/current way of thinking is certainly counterproductive for any new scientific developments and innovations.

Non-inferiority between follitropin delta (REKOVELLE®) and follitropin alfa for ongoing pregnancy rate and ongoing implantation rate was designed to be assessed for the overall trial population (N=1,326 patients), not in sub-populations characterized by age or other parameters. For the readers not familiar with the style of Assessment Reports prepared by the European Medicines Agency, these documents summarize the findings and questions raised during the review process, the corresponding responses provided by the Sponsor (in this case Ferring Pharmaceuticals) and finally the conclusions. Merck makes reference to a sentence on “some heterogeneity of responses” in the Assessment Report (6) made early on by the assessor when reviewing the data. Despite what seems to be an intense and detailed reading of the Assessment Report, the Merck executives appear to have overlooked that the European Medicines Agency assessor four lines further ahead states that “complementary information… was provided” and concludes “non-inferiority of FE 999049 over Gonal-F was accepted” (note: FE 999049 being the internal compound name for follitropin delta) and finally “In conclusion, the CHMP considered the efficacy of follitropin delta established” (CHMP: Committee for Medicinal Products for Human Use) (6). Furthermore, it is unfortunate that this evaluation and conclusion went unnoticed, as this would have saved Merck bringing forward hypotheses or claims based on a phase 2 trial with merely 43 patients exposed to GONAL-F.

We find the reporting of secondary outcomes, including the ones pointed out by the Merck executives, i.e. live birth, ovarian response, embryology data, and early and late OHSS and/or preventive interventions for early OHSS, appropriate and clinically relevant. Live birth rates are critical to patients and clinicians and presenting data on this provides reassurance that unforeseen events have not occurred during the second and third trimester. The dosing algorithm for follitropin delta was specifically designed to modulate the ovarian response, so naturally these data are presented. Embryology data are informative to clinicians and other laboratory members of the multidisciplinary team, hence them usually being included in publications on gonadotropin trials. It is important to report the safety profile associated with this new treatment modality, including the frequency of early and late OHSS and/or preventive interventions for early OHSS.

Finally, we must once again stress that non-inferiority of follitropin delta versus follitropin alfa has been established for ongoing pregnancy and ongoing implantation, as concluded by the European Medicines Agency. Regulatory bodies governing the health care profession hold the highest authority in assessing new medicines, and we are disappointed that the Merck executives aim to undermine rather than respect such evaluations.

Ferring will continue its pursuit to expand the knowledge on gonadotropins by investing and conducting clinical trials compliant with the highest regulatory and scientific standards and to publish our research in peer-reviewed journals and thereby to bring forward safe and efficacious medicines within reproductive health.

References
1. EMD Serono. Full prescribing information for Gonal-F® RFF Redi-ject™. http://www.emdserono.com/ms.country.us/en/images/Gonal-f_RFF_Redi-ject_PI_tcm115_140008.pdf?Version=

2. EMD Serono. Full prescribing information for Gonal-F® Multidose. http://www.emdserono.com/ms.country.us/en/images/Gonal-f_Multidose_PI_tcm115_140005.pdf?Version=

3. EMD Serono. Full prescribing information for GONAL-F RFF. http://www.emdserono.com/ms.country.us/en/images/Gonal-f_RFF_75_IU_PI_tcm115_140009.pdf?Version=

4. EMD Serono. Product Monograph for Gonal-f® Pen.
http://www.medical-information.ca/wp-content/uploads/2017/05/GONAL-f-PEN-EPM-May-2017.pdf

5. Ferring Pharmaceuticals. Summary of Product Characteristics for follitropin delta (REKOVELLE®). http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003994/WC500220235.pdf

6. European Medicines Agency. Assessment Report for follitropin delta (REKOVELLE®). http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003994/WC500220237.pdf

Go to the profile of Jack Wilkinson
Jack Wilkinson over 3 years ago

Jack Wilkinson, Centre for Biostatistics,Institute of Population Health, Manchester Academic Health Science Centre (MAHSC), University of Manchester, Manchester, UK.


Sarah Lensen, Department of Obstetrics and Gynaecology, University of Auckland, New Zealand.


Nyboe Andersen and colleagues (2017) present a large randomised study comparing follitropin delta, with dosing based on AMH and body weight, against follitropin alfa, with dose selection by conventional means. Stated key findings of the study include the fact that more women achieved a target response of 8-14 oocytes (43.3% vs 38.4%) in the follitropin delta group, and that fewer women had poor (< 4 oocytes) or excessive (>= 15 or >= 20 oocytes) responses compared to the follitropin alfa group. However, on close inspection of the published study, it is not clear that follitropin delta, administered using this dose selection algorithm, has been shown to be superior to the standard dose of follitropin alfa in relation to response to stimulation. 


We note that calculations regarding number of oocytes obtained do not include women who were randomised but subsequently had their stimulation cycle cancelled for anticipated poor response (prior to hCG trigger). Indeed, there were more women with cycles cancelled for anticipated poor response in the follitropin delta group than the follitropin alfa group. The claim that poor response was lower in the follitropin delta arm then appears to be technically correct but potentially highly misleading. It would be preferable to include women with cancelled cycles in the numerator and denominator (they appeared in neither numerator nor denominator in the analysis presented by Nyboe Andersen and colleagues) by setting the number of oocytes recovered for women with cancelled stimulation cycles to be zero. This would rectify any bias resulting from differential cancellation rates between the study arms. It would also preserve the balance over confounding factors produced by randomisation, which is otherwise violated. When we include all patients in this way, the mean number of oocytes retrieved in the follitropin delta and follitropin alfa arms is 9.6 and 10.1, respectively, and the numbers achieving the target response are 275 (41%) and 247 (37%), which gives p=0.15 from a chi-squared test. 


A second concern is the fact that the authors present the rate of poor response in the low AMH group and the rate of hyper response in the high AMH group, but do not present the rate of poor response in the high AMH group or the rate of hyper response in the low AMH group. If we refer to hyper responses in low AMH patients and poor responses in high AMH patients as ‘inverted’, then we can calculate the number of inverted responses in each group. In fact, the number of inverted responses are greater in the follitropin delta group (5% vs 4% using 15 oocytes as the threshold for hyper response, or 4% vs 2% using 20 oocytes):


           
Number Inverted <4 or >=15 is 34/640 (5%) in experimental arm and 25/643 (4%) in the control arm, p=0.233 from Fisher's exact test.        
Number Inverted <4 or >=20 is 23/640 (4%) in experimental arm and 11/643 (2%) in the control arm, p=0.038 from       Fisher’s exact test.


These calculations are conducted in patients achieving hCG trigger, as it does not appear to be possible to identify whether the women with cycles cancelled for poor response were in the high or low AMH stratum from the information presented. The number of hyper responses in the low AMH group is of particular interest, since this represents increased risk to the treated woman and any resulting offspring. Unfortunately, this information is obfuscated by the presentation in the manuscript. We also note that the decision to report the rates of hypo and hyper response only in these subgroups appears to be a departure from the clinicaltrials.gov record for the trial (https://clinicaltrials.gov/ct2/show/NCT01956110).


Given that the claim of the authors in relation to the effectiveness of treatment was one of non-inferiority, the matter of the safety of the individualised dosing regimen compared to standard dosing would appear to be of paramount importance. On the basis of the considerations outlined above, it is unclear that an advantage of the individualised follitropin delta regimen in relation to achieving target ovarian responses has been demonstrated. Moreover, the data leave open the possibility that the individualised regimen may increase excessive responses in low AMH patients. We would like to invite the authors to clarify this point. 


A version of this comment has been posted on Pubmed Commons.


References
Nyboe Andersen, A., et al. (2017). "Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial." Fertil Steril 107(2): 387-396 e384.


Conflict of interest statement


JW is funded by a Doctoral Research Fellowship from the National Institute for Health Research (DRF-2014-07-050). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. JW also declares that publishing research is beneficial to his career. JW is a statistical editor for the Cochrane Gynaecology and Fertility Group, although the views expressed here are not necessarily those of the group.

Go to the profile of Bjarke Mirner Klein, PhD
Bjarke Mirner Klein, PhD about 3 years ago

Bjarke Mirner Klein, PhD, Director, Biometrics, Ferring Pharmaceuticals, Copenhagen, Denmark.  


We thank the authors for their interest in our trial. This publication is the first reporting data from the ESTHER-1 trial and therefore presents the overall results at a high level. More publications presenting full details on different aspects of the data are in progress. In their comment, they raise the following three concerns: 1) the presentation of the number of oocytes retrieved, 2) the decision not to present the so-called ‘inverted’ responders, and 3) the possibility that the individualised dosing regimen may increase excessive response in low AMH patients. Each of these will be addressed in the following.

Concerning the presentation of the number of oocytes retrieved: Strict criteria for cycle cancellation due to poor or excessive response were specified in the trial protocol. Since a priori both scenarios were considered a possibility and since there is no consensus on how the number of oocytes retrieved should be imputed for each scenario it was decided to present the data as in Table 3. This is a transparent way of presenting the results since the reader can derive the numbers for all subjects using his/her own assumptions on how to impute the cycle cancellations. This is exactly what the two authors have done assuming that cycle cancellations due to poor response should be included as zero oocytes retrieved in the calculations. It should be noted that the treatment difference remains the same irrespective of method of display.   

Concerning the ‘inverted’ responders: The terminology of ‘inverted’ ovarian response may be misunderstood, since it may suggest that e.g. a subject who would have <4 oocytes retrieved using a standard starting dose of follitropin alfa (GONAL-F) would have ≥20 oocytes retrieved with the individualised follitropin delta (REKOVELLE®) dose. This would indeed be a dramatic and surprising impact considering that the maximum daily dose of follitropin delta is 12 mcg and the starting dose of follitropin alfa is 150 IU (11 mcg). However, as illustrated on Figures 1A and 1B the consequences of the individualised follitropin delta (REKOVELLE®) dosing regimen dose are not that drastic. From these figures, it can be observed that the ovarian response in terms of number of oocyte retrieved is comparable for the mid-range AMH while the treatment differences are seen at the lower and higher AMH level. 

Since the individualised dosing algorithm assigns the same daily dose of individualised follitropin delta (REKOVELLE®) to subjects with an AMH <15 pmol/L and gradually decreases the dose as a function of AMH for subjects with AMH ≥15 pmol/L it seems relevant to present the data by these subgroups. As can be seen from Table 3, the individualised follitropin delta (REKOVELLE®) dosing regimen shifts the distribution of oocytes retrieved upwards for subjects with AMH <15 pmol/L while it shifts the distribution downwards for subjects  with AMH ≥15 pmol/L. Such a shift in the distribution obviously also affects the tails of the distribution, i.e. in this case the probability of either too low or too high number of oocytes retrieved. For the publication, it was considered relevant to focus on the risk of poor response in the subjects at risk of hypo-response and the risk of excessive response for the subjects at risk of hyper-response.

Concerning the possibility that the individualised dosing regimen may increase excessive response in low AMH patients: Relevant data on OHSS and preventive interventions is presented in Table 3 and the relationship to AMH is illustrated in Figure 1C. The authors are concerned that since excessive response is not presented for the potential hypo-responders (AMH <15 pmol/L) the overall safety of the individualised dosing is unclear. We take the opportunity to present the data for excessive response in the subjects at risk of hypo-response, where the observed incidence of having ≥15 oocytes retrieved among subjects with AMH <15 pmol/L was (6%) and (5%) in the follitropin delta and follitropin alfa groups, respectively.