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InfertilityPhase 4INTENS-EQNCT04983173

INTEnsity of ovariaN Stimulation and Embryo Quality

A Phase 4 study testing Ovarian Stimulation with CC+rFSH and Ovarian Stimulation with rFSH in people with Infertility, run by Fundación Santiago Dexeus Font at 1 site in Spain.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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. Read more about this study

Who is it for?
Ages 35 to 40 years, women only
Conditions the study is for
Infertility
What is being tested?
Ovarian Stimulation with CC+rFSH and Ovarian Stimulation with rFSH
Could I receive a placebo?
No, everyone receives an active treatment
How many people
110 participants
Where
1 siteSpain
Study dates
23 Nov 2021to 11 Mar 2026
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 35 to 40 years
  • Women only
  • No healthy volunteers
  • Adult

Who may be able to join

  • 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

Who cannot join

  • 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).

Trial locations and contacts

1 site in 1 country.

Spain1 site

  • Salud de la Mujer Dexeus

    Barcelona, 08028

Other trials in Spain

About this study

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

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).

Read the detailed 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).

Conditions
Infertility
Being tested
Ovarian Stimulation with CC+rFSH, Ovarian Stimulation with rFSH
Medical subject headings
Infertility

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Ovarian Stimulation with CC+rFSHDrug

    : 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 rFSHDrug

    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®)

Study groups in NCT04983173
Study groupRoleWhat they receive
Experimental: Clomiphene Citrate (CC) + rFSHExperimentalOvarian Stimulation with CC+rFSH
Receives: Drug: Ovarian Stimulation with CC+rFSH
rFSHActive comparatorOvarian Stimulation with rFSH
Receives: Drug: Ovarian Stimulation with rFSH

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of good quality blastocysts

    Measured: Until 5, 6 or 7 days after oocyte pick-up

Secondary outcomes (31)

  1. Change in Progesterone values

    Measured: days 1, 6, 8, 10 and the day of ovulation triggering

  2. Change in Estradiol values

    Measured: days 1, 6, 8, 10 and the day of ovulation triggering

  3. Change in FSH Values

    Measured: days 1, 6, 8, 10 and the day of ovulation triggering

  4. Change in LH values

    Measured: days 1, 6, 8, 10 and the day of ovulation triggering

  5. Length of ovarian stimulation

    Measured: 7 -20 days from initiation of ovarian stimulation

  6. Number of oocytes retrieved

    Measured: 7 -20 days from initiation of ovarian stimulation

  7. Number of mature oocytes (MIIs) retrieved

    Measured: 7 -20 days from initiation of ovarian stimulation

  8. Follicle to Oocyte Index (FOI)

    ratio of the number of preovulatory follicles and the number of antral follicles available at the start of stimulation

    Measured: 7 -20 days from initiation of ovarian stimulation

  9. Total dose of rFSH

    Measured: 7 -20 days from initiation of ovarian stimulation

  10. Follicular Output Rate (FORT)

    ratio of the number of preovulatory follicles and the number of antral follicles available at the start of stimulation

    Measured: 7 -20 days from initiation of ovarian stimulation

  11. Cycle cancelation rate

    when no follicle has adequate maturation, or the follicle is lost due to spontaneous LH surge

    Measured: Until 15 days after the beginning of ovarian stimulation

  12. Reason for cycle cancelation

    Measured: Until 15 days after the beginning of ovarian stimulation

  13. Fertilization rate

    Measured: One day after oocyte pick-up

  14. Time of appearance of the 2nd polar body (tPB2)

    Measured: One day after oocyte pick-up

  15. Time of pronuclei appearance (tPNa)

    Measured: One day after oocyte pick-up

  16. Evaluation of both pronuclei (PN)

    Measured: One day after oocyte pick-up

  17. Time of pronuclei disappearance (tPNf)

    Measured: Day 2 after insemination

  18. Time of division from 2 to 8 cells (t2, t3, t4, t5, t6, t7, t8)

    Measured: Until Day 2 Day 3 after insemination

  19. Time of compactation (tSC)

    Measured: Until Day 3 Day 6 after insemination

  20. Time of morula (tM)

    Measured: Until Day 3 Day 6 after insemination

  21. Time of cavitation (tSB)

    Measured: Until 5, 6 or 7 days after insemination

  22. Time of full blastulation (tB)

    Measured: Until 5, 6 or 7 days after insemination

  23. Time of expanded blastocyst (tEB)

    Measured: Until 5, 6 or 7 days after insemination

  24. Time of hatched blastocyst (tHB)

    Measured: Until 5, 6 or 7 days after insemination

  25. Time of embryo discarding (tDead)

    Measured: Until 7 days after insemination

  26. Total number of embryos

    Measured: Until 5, 6 or 7 days after insemination

  27. Blastocyst formation rate

    Measured: Until 5, 6 or 7 days after insemination

  28. Number of embryos cryopreserved

    Measured: Until 5, 6 or 7 days after insemination

  29. Embryo stage (D5, D6, D7)

    Measured: Until 5, 6 or 7 days after insemination

  30. Clinical pregnancy rate

    defined as a viable intrauterine pregnancy of at least 8-10 weeks duration confirmed on an ultrasound scan

    Measured: 5 to 6 weeks after oocyte pick-up

  31. Ongoing pregnancy rate

    Measured: 8 to 10 weeks after oocyte pick-up

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Jul 2021
  2. Study start23 Nov 2021
  3. Primary completion11 Mar 2026
  4. Study completion11 Mar 2026

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
110 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04983173
Sponsor's protocol ID
FSD-IEQ-2021-03
Other IDs
2021-000941-42
Acronym
INTENS-EQ
Status last verified
Apr 2026
First submitted
5 Jul 2021
Last updated
14 Apr 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 17855409

  • 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.

    PubMed 9111183

  • 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.

    PubMed 28236310

  • 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.

    PubMed 29096046

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

  • 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.

    PubMed 26259908

  • 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.

    PubMed 18544578

  • 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.

    PubMed 17336650

  • 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.

    PubMed 21987524

  • 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.

    PubMed 27054309

  • 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.

    PubMed 32830232

  • 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.

    PubMed 29121326

  • 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.

    PubMed 19091754

  • 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.

    PubMed 24192422

  • 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.

    PubMed 20843965

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Ovarian Stimulation with CC+rFSH and Ovarian Stimulation with rFSH in people with Infertility, run by Fundación Santiago Dexeus Font at 1 site in Spain.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 14 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of good quality blastocysts (time frame: Until 5, 6 or 7 days after oocyte pick-up). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04983173, which also lists 29 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Apr 2026.

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