INTEnsity of ovariaN Stimulation and Embryo Quality

Infertility Clinical Trial

— INTENS-EQ  

Official title:

The Impact of the Intensity of Ovarian Stimulation on Embryo Quality in Predicted Suboptimal Responders. A Randomized Controlled Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04983173
• Other study ID #: FSD-IEQ-2021-03
• Secondary ID: 2021-000941-42
• Status: Recruiting
• Phase: Phase 4
• Start date: November 23, 2021
• Est. completion date: June 2026

Study information

• Verified date: March 2024
• Source: Institut Universitari Dexeus
• Contact: Nikolaos P Polyzos, MD PhD
• Phone: 0034932274700
• Email: nikpol[@]dexeus.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The management of suboptimal ovarian responders remains a challenging task in IVF. These patients are frequently managed with an intense stimulation protocol of ovarian stimulation in order obtain the maximum number of embryos and, therefore, maximize the cumulative live birth rate. However, the concept of "the more the better" has been recently defied by the one of "mild stimulation". Defenders of this protocol state that with mild stimulation only the best quality oocytes are allowed to grow and, therefore, higher quality embryos will be obtained. However, the impact of the intensity of ovarian stimulation on embryo quality is far from consensual. Moreover, its effect on early embryo development has never been evaluated.

Therefore, the investigators set out to perform this randomized controlled trial comparing the number of GQB and the morphokinetic parameters of early embryo development in infertile patients undergoing two different intensities of ovarian stimulation, a milder approach (CC plus 150 IU daily dose of rFSH) and a more intense approach (300 IU daily dose of rFSH).

Description:

Despite the lack of a consistent definition for "mild stimulation" (MS), the International Society for Mild Approaches in Assisted Reproduction defined it as a protocol performed with gonadotropins, alone or with oral compounds, at lower doses or for a shorter duration, with the aim of achieving 2-7 oocytes. One of the strategies proposed for MS is the use of Clomiphene Citrate (CC). CC acts as a selective estrogen-receptor modulator. By blocking estrogen receptors in the hypothalamic arcuate nucleus, it increases the production of gonadotropin-releasing hormone (GnRH) and, as a result, FSH and luteinizing hormone (LH). Moreover, CC increases the pituitary sensitivity to GnRH and granulosa cell sensitivity to pituitary gonadotropins. Taking these actions into account, several protocols have adopted a combination of CC and exogenous gonadotropins with the aim of improving follicular recruitment and, therefore, ovarian response to stimulation, in patients undergoing in vitro fertilization (IVF). The available evidence has allowed for the inclusion of CC in international guidelines as a treatment option, alone or in combination with gonadotropins, equally recommended in the management of poor responders when compared to gonadotropin stimulation alone.

The concept behind MS is that, with this approach, only the healthier follicles with higher quality oocytes are allowed to grow. Proponents of this protocol state that MS reduces the risk of multiple pregnancy and ovarian hyperstimulation syndrome (OHSS), as well as patient dropout rate and treatment costs. However, evidence regarding clinical outcomes is far from consensual. The best available evidence regarding MS in predicted poor responders comes from the OPTIMIST trial, showing no difference in the cumulative live birth rates when a mild approach, using 150 IU of rFSH, was compared to an individualized protocol of 225/450 IU rFSH. However, several methodological inconsistencies have been pointed out in this randomized controlled trial. In particular, a black hole was left in the management of predicted low responders with an intermediate prognosis (antral follicle count between 8-10), taking into account the allowance for dose adjustments in the second cycle in the 150 IU group. Considering that the control group was treated with rFSH 225 IU daily, a comparison of two identical doses might have been provided.

Evidence regarding the effect of MS on embryo quality is also conflicting. Baart et al. first reported a lower aneuploidy rate following MS when compared to conventional protocols and concluded that mitotic segregation errors might increase with growing gonadotropin dosages. However, this has not been confirmed in recent studies. As for the number of good quality embryos, while previous studies have shown no difference regarding MS and conventional protocols, Vermey et al found a positive correlation between the number of retrieved oocytes and the embryo quality.

Although these previous studies provide some valuable information, the heterogeneity of the available evidence cannot be disregarded. Moreover, to the best our knowledge, the effect of the intensity of ovarian stimulation on early embryo development has not been previously described. Therefore, the investigators set out to perform this randomized controlled trial comparing the number of good quality blastocysts (GQB) and morphokinetic parameters of early embryo development in patients with a predicted suboptimal ovarian response undergoing two different intensities of ovarian stimulation, a milder (CC 50 mg/day from cycle D2-6 + rFSH 150 IU daily from D2 onwards) and a more intense approach (300 IU daily dose of rFSH starting on cycle D2).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 110
• Est. completion date: June 2026
• Est. primary completion date: December 2025
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 35 Years to 40 Years

Eligibility

Inclusion Criteria:

• Able and willing to sign the Patient Consent Form and adhere to study visitation schedule

• Antral follicle count (AFC) = 5 and = 10

• Anti-Mullerian hormone (AMH) =1.5 ng/ml (AMH result of up to one year will be valid)

• Age = 35 years and =40 years

• BMI =18.5 and <25 kg/m2

Exclusion Criteria:

• AFC >10

• History of untreated autoimmune, endocrine or metabolic disorders

• Contraindication for hormonal treatment

• Preimplantation genetic diagnosis cycles

• Severe male factor (sperm concentration <5 M/mL)

• Recent history of severe disease requiring regular treatment (clinically significant concurrent medical condition that could compromise subject safety or interfered with the trial assessment and patients with any contraindication of being pregnant).

Related Conditions & MeSH terms

• Infertility

Intervention

Drug:
• Ovarian Stimulation with CC+rFSH
: CC 50 mg/day (Omifin®) + rFSH 150 IU (Ovaleap®) GnRH antagonist: ganirelix 0.25 mg (Orgalutran®) Recombinant human chorionic gonadotropin (rhCG) 250 µg (Ovitrelle®) micronized progesterone 200 mg 3id (Utrogestan®)
• Ovarian Stimulation with rFSH
rFSH 300 IU rFSH (Ovaleap®) GnRH antagonist: ganirelix 0.25 mg (Orgalutran®) Recombinant human chorionic gonadotropin (rhCG) 250 µg (Ovitrelle®) micronized progesterone 200 mg 3id (Utrogestan®)

Locations

Country	Name	City	State
Spain	Salud de la Mujer Dexeus	Barcelona

Sponsors (1)

Lead Sponsor	Collaborator
Fundación Santiago Dexeus Font

Country where clinical trial is conducted

Spain, 

References & Publications (29)

Aleyamma TK, Kamath MS, Muthukumar K, Mangalaraj AM, George K. Affordable ART: a different perspective. Hum Reprod. 2011 Dec;26(12):3312-8. doi: 10.1093/humrep/der323. Epub 2011 Oct 10. — View Citation

Alpha Scientists in Reproductive Medicine and ESHRE Special Interest Group of Embryology. The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Hum Reprod. 2011 Jun;26(6):1270-83. doi: 10.1093/humrep/der037. Epub 2011 Apr 18. — View Citation

Baart EB, Martini E, Eijkemans MJ, Van Opstal D, Beckers NG, Verhoeff A, Macklon NS, Fauser BC. Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial. Hum Reprod. 2007 Apr;22(4):980-8. doi: 10.1093/humrep/del484. Epub 2007 Jan 4. — View Citation

Bechtejew TN, Nadai MN, Nastri CO, Martins WP. Clomiphene citrate and letrozole to reduce follicle-stimulating hormone consumption during ovarian stimulation: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2017 Sep;50(3):315-323. doi: 10.1002/uog.17442. Epub 2017 Aug 10. — View Citation

Datta AK, Maheshwari A, Felix N, Campbell S, Nargund G. Mild versus conventional ovarian stimulation for IVF in poor, normal and hyper-responders: a systematic review and meta-analysis. Hum Reprod Update. 2021 Feb 19;27(2):229-253. doi: 10.1093/humupd/dmaa035. — View Citation

Dickey RP, Holtkamp DE. Development, pharmacology and clinical experience with clomiphene citrate. Hum Reprod Update. 1996 Nov-Dec;2(6):483-506. doi: 10.1093/humupd/2.6.483. — View Citation

ESHRE Reproductive endocrinology guidelines group. Ovarian Stimulation for IVF / ICSI - Guideline of the European Society of Human Reproduction and Embryology. Belgium: ESHRE; 2019

ESHRE Special Interest Group of Embryology and Alpha Scientists in Reproductive Medicine. Electronic address: coticchio.biogenesi@grupposandonato.it. The Vienna consensus: report of an expert meeting on the development of ART laboratory performance indicators. Reprod Biomed Online. 2017 Nov;35(5):494-510. doi: 10.1016/j.rbmo.2017.06.015. Epub 2017 Aug 4. — View Citation

Ghosh Dastidar S, Maity S, Ghosh Dastidar B. Reappraisal of IVF stimulation in good prognosis patients - a prospective randomized study to compare mild versus standard long protocol. Fertil Steril [Internet]. 2010;94(4):S28. Available from: http://dx.doi.org/10.1016/j.fertnstert.2010.07.108

Golan A, Weissman A. Symposium: Update on prediction and management of OHSS. A modern classification of OHSS. Reprod Biomed Online. 2009 Jul;19(1):28-32. doi: 10.1016/s1472-6483(10)60042-9. — View Citation

Heijnen EM, Eijkemans MJ, De Klerk C, Polinder S, Beckers NG, Klinkert ER, Broekmans FJ, Passchier J, Te Velde ER, Macklon NS, Fauser BC. A mild treatment strategy for in-vitro fertilisation: a randomised non-inferiority trial. Lancet. 2007 Mar 3;369(9563):743-749. doi: 10.1016/S0140-6736(07)60360-2. — View Citation

Hohmann FP, Macklon NS, Fauser BC. A randomized comparison of two ovarian stimulation protocols with gonadotropin-releasing hormone (GnRH) antagonist cotreatment for in vitro fertilization commencing recombinant follicle-stimulating hormone on cycle day 2 or 5 with the standard long GnRH agonist protocol. J Clin Endocrinol Metab. 2003 Jan;88(1):166-73. doi: 10.1210/jc.2002-020788. — View Citation

Irani M, Canon C, Robles A, Maddy B, Gunnala V, Qin X, Zhang C, Xu K, Rosenwaks Z. No effect of ovarian stimulation and oocyte yield on euploidy and live birth rates: an analysis of 12 298 trophectoderm biopsies. Hum Reprod. 2020 May 1;35(5):1082-1089. doi: 10.1093/humrep/deaa028. — View Citation

Kamath MS, Maheshwari A, Bhattacharya S, Lor KY, Gibreel A. Oral medications including clomiphene citrate or aromatase inhibitors with gonadotropins for controlled ovarian stimulation in women undergoing in vitro fertilisation. Cochrane Database Syst Rev. 2017 Nov 2;11(11):CD008528. doi: 10.1002/14651858.CD008528.pub3. — View Citation

La Marca A, Minasi MG, Sighinolfi G, Greco P, Argento C, Grisendi V, Fiorentino F, Greco E. Female age, serum antimullerian hormone level, and number of oocytes affect the rate and number of euploid blastocysts in in vitro fertilization/intracytoplasmic sperm injection cycles. Fertil Steril. 2017 Nov;108(5):777-783.e2. doi: 10.1016/j.fertnstert.2017.08.029. Epub 2017 Oct 4. — View Citation

Matsaseng T, Kruger T, Steyn W. Mild ovarian stimulation for in vitro fertilization: are we ready to change? A meta-analysis. Gynecol Obstet Invest. 2013;76(4):233-40. doi: 10.1159/000355980. Epub 2013 Nov 2. — View Citation

Montoya-Botero P, Martinez F, Rodriguez-Purata J, Rodriguez I, Coroleu B, Polyzos NP. Erratum. The effect of type of oral contraceptive pill and duration of use on fresh and cumulative live birth rates in IVF/ICSI cycles. Hum Reprod. 2021 Mar 18;36(4):1159-1161. doi: 10.1093/humrep/deaa358. No abstract available. — View Citation

Nargund G, Fauser BC, Macklon NS, Ombelet W, Nygren K, Frydman R; Rotterdam ISMAAR Consensus Group on Terminology for Ovarian Stimulation for IVF. The ISMAAR proposal on terminology for ovarian stimulation for IVF. Hum Reprod. 2007 Nov;22(11):2801-4. doi: 10.1093/humrep/dem285. Epub 2007 Sep 12. — View Citation

Paulson RJ, Fauser BCJM, Vuong LTN, Doody K. Can we modify assisted reproductive technology practice to broaden reproductive care access? Fertil Steril. 2016 May;105(5):1138-1143. doi: 10.1016/j.fertnstert.2016.03.013. Epub 2016 Apr 4. — View Citation

Polyzos NP, Popovic-Todorovic B. SAY NO to mild ovarian stimulation for all poor responders: it is time to realize that not all poor responders are the same. Hum Reprod. 2020 Sep 1;35(9):1964-1971. doi: 10.1093/humrep/deaa183. — View Citation

Sterrenburg MD, Veltman-Verhulst SM, Eijkemans MJ, Hughes EG, Macklon NS, Broekmans FJ, Fauser BC. Clinical outcomes in relation to the daily dose of recombinant follicle-stimulating hormone for ovarian stimulation in in vitro fertilization in presumed normal responders younger than 39 years: a meta-analysis. Hum Reprod Update. 2011 Mar-Apr;17(2):184-96. doi: 10.1093/humupd/dmq041. Epub 2010 Sep 15. — View Citation

van Tilborg TC, Torrance HL, Oudshoorn SC, Eijkemans MJC, Koks CAM, Verhoeve HR, Nap AW, Scheffer GJ, Manger AP, Schoot BC, Sluijmer AV, Verhoeff A, Groen H, Laven JSE, Mol BWJ, Broekmans FJM; OPTIMIST study group. Individualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 1: The predicted poor responder. Hum Reprod. 2017 Dec 1;32(12):2496-2505. doi: 10.1093/humrep/dex318. — View Citation

Venetis CA, Tilia L, Panlilio E, Kan A. Is more better? A higher oocyte yield is independently associated with more day-3 euploid embryos after ICSI. Hum Reprod. 2019 Jan 1;34(1):79-83. doi: 10.1093/humrep/dey342. — View Citation

Verberg MF, Eijkemans MJ, Heijnen EM, Broekmans FJ, de Klerk C, Fauser BC, Macklon NS. Why do couples drop-out from IVF treatment? A prospective cohort study. Hum Reprod. 2008 Sep;23(9):2050-5. doi: 10.1093/humrep/den219. Epub 2008 Jun 10. — View Citation

Verberg MF, Eijkemans MJ, Macklon NS, Heijnen EM, Baart EB, Hohmann FP, Fauser BC, Broekmans FJ. The clinical significance of the retrieval of a low number of oocytes following mild ovarian stimulation for IVF: a meta-analysis. Hum Reprod Update. 2009 Jan-Feb;15(1):5-12. doi: 10.1093/humupd/dmn053. — View Citation

Vermey BG, Chua SJ, Zafarmand MH, Wang R, Longobardi S, Cottell E, Beckers F, Mol BW, Venetis CA, D'Hooghe T. Is there an association between oocyte number and embryo quality? A systematic review and meta-analysis. Reprod Biomed Online. 2019 Nov;39(5):751-763. doi: 10.1016/j.rbmo.2019.06.013. Epub 2019 Jul 3. — View Citation

Wu Q, Li H, Zhu Y, Jiang W, Lu J, Wei D, Yan J, Chen ZJ. Dosage of exogenous gonadotropins is not associated with blastocyst aneuploidy or live-birth rates in PGS cycles in Chinese women. Hum Reprod. 2018 Oct 1;33(10):1875-1882. doi: 10.1093/humrep/dey270. — View Citation

Zegers-Hochschild F, Adamson GD, Dyer S, Racowsky C, de Mouzon J, Sokol R, Rienzi L, Sunde A, Schmidt L, Cooke ID, Simpson JL, van der Poel S. The International Glossary on Infertility and Fertility Care, 2017. Fertil Steril. 2017 Sep;108(3):393-406. doi: 10.1016/j.fertnstert.2017.06.005. Epub 2017 Jul 29. — View Citation

Zhang JJ, Merhi Z, Yang M, Bodri D, Chavez-Badiola A, Repping S, van Wely M. Minimal stimulation IVF vs conventional IVF: a randomized controlled trial. Am J Obstet Gynecol. 2016 Jan;214(1):96.e1-8. doi: 10.1016/j.ajog.2015.08.009. Epub 2015 Aug 8. — View Citation

* Note: There are 29 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Ovarian hyperstimulation syndrome (OHSS) (percent)	Number of subjects with OHSS during the ovarian stimulation period and their severity	Until 15 days after the end of ovarian stimulation
Other	Miscarriages	any spontaneous abortion that occurred after confirmation of clinical pregnancy	before completion of 12 weeks of gestation
Other	Incidence of adverse events and serious adverse events		Until 15 days after the end of ovarian stimulation
Primary	Number of good quality blastocysts		Until 5, 6 or 7 days after oocyte pick-up
Secondary	Change in Progesterone values		days 1, 6, 8, 10 and the day of ovulation triggering
Secondary	Change in Estradiol values		days 1, 6, 8, 10 and the day of ovulation triggering
Secondary	Change in FSH Values		days 1, 6, 8, 10 and the day of ovulation triggering
Secondary	Change in LH values		days 1, 6, 8, 10 and the day of ovulation triggering
Secondary	Length of ovarian stimulation		7 -20 days from initiation of ovarian stimulation
Secondary	Number of oocytes retrieved		7 -20 days from initiation of ovarian stimulation
Secondary	Number of mature oocytes (MIIs) retrieved		7 -20 days from initiation of ovarian stimulation
Secondary	Follicle to Oocyte Index (FOI)	ratio of the number of preovulatory follicles and the number of antral follicles available at the start of stimulation	7 -20 days from initiation of ovarian stimulation
Secondary	Total dose of rFSH		7 -20 days from initiation of ovarian stimulation
Secondary	Follicular Output Rate (FORT)	ratio of the number of preovulatory follicles and the number of antral follicles available at the start of stimulation	7 -20 days from initiation of ovarian stimulation
Secondary	Cycle cancelation rate	when no follicle has adequate maturation, or the follicle is lost due to spontaneous LH surge	Until 15 days after the beginning of ovarian stimulation
Secondary	Reason for cycle cancelation		Until 15 days after the beginning of ovarian stimulation
Secondary	Fertilization rate		One day after oocyte pick-up
Secondary	Time of appearance of the 2nd polar body (tPB2)		One day after oocyte pick-up
Secondary	Time of pronuclei appearance (tPNa)		One day after oocyte pick-up
Secondary	Evaluation of both pronuclei (PN)		One day after oocyte pick-up
Secondary	Time of pronuclei disappearance (tPNf)		Day 2 after insemination
Secondary	Time of division from 2 to 8 cells (t2, t3, t4, t5, t6, t7, t8)		Until Day 2 Day 3 after insemination
Secondary	Time of compactation (tSC)		Until Day 3 Day 6 after insemination
Secondary	Time of morula (tM)		Until Day 3 Day 6 after insemination
Secondary	Time of cavitation (tSB)		Until 5, 6 or 7 days after insemination
Secondary	Time of full blastulation (tB)		Until 5, 6 or 7 days after insemination
Secondary	Time of expanded blastocyst (tEB)		Until 5, 6 or 7 days after insemination
Secondary	Time of hatched blastocyst (tHB)		Until 5, 6 or 7 days after insemination
Secondary	Time of embryo discarding (tDead)		Until 7 days after insemination
Secondary	Total number of embryos		Until 5, 6 or 7 days after insemination
Secondary	Blastocyst formation rate		Until 5, 6 or 7 days after insemination
Secondary	Number of embryos cryopreserved		Until 5, 6 or 7 days after insemination
Secondary	Embryo stage (D5, D6, D7)		Until 5, 6 or 7 days after insemination
Secondary	Clinical pregnancy rate	defined as a viable intrauterine pregnancy of at least 8-10 weeks duration confirmed on an ultrasound scan	5 to 6 weeks after oocyte pick-up
Secondary	Ongoing pregnancy rate		8 to 10 weeks after oocyte pick-up

External Links

•   Department of Obstetrics, Gynaecology and Reproduction Hospital Universitari Quiron Dexeus