INTEnsity of ovariaN Stimulation and Embryo Quality (INTENS-EQ)

April 13, 2026 updated by: Fundación Santiago Dexeus Font

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).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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).

Study Type

Interventional

Enrollment (Actual)

110

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Spain
      • Barcelona, Spain, 08028
        • Salud de la Mujer Dexeus

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

35 years to 40 years (Adult)

Accepts Healthy Volunteers

No

Description

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).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Experimental: Clomiphene Citrate (CC) + rFSH
Ovarian Stimulation with CC+rFSH
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®)
Active Comparator: rFSH
Ovarian Stimulation with rFSH
Drug: 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®)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Number of good quality blastocysts
Time Frame: Until 5, 6 or 7 days after oocyte pick-up
Until 5, 6 or 7 days after oocyte pick-up

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Progesterone values
Time Frame: days 1, 6, 8, 10 and the day of ovulation triggering
days 1, 6, 8, 10 and the day of ovulation triggering
Change in Estradiol values
Time Frame: days 1, 6, 8, 10 and the day of ovulation triggering
days 1, 6, 8, 10 and the day of ovulation triggering
Change in FSH Values
Time Frame: days 1, 6, 8, 10 and the day of ovulation triggering
days 1, 6, 8, 10 and the day of ovulation triggering
Change in LH values
Time Frame: days 1, 6, 8, 10 and the day of ovulation triggering
days 1, 6, 8, 10 and the day of ovulation triggering
Length of ovarian stimulation
Time Frame: 7 -20 days from initiation of ovarian stimulation
7 -20 days from initiation of ovarian stimulation
Number of oocytes retrieved
Time Frame: 7 -20 days from initiation of ovarian stimulation
7 -20 days from initiation of ovarian stimulation
Number of mature oocytes (MIIs) retrieved
Time Frame: 7 -20 days from initiation of ovarian stimulation
7 -20 days from initiation of ovarian stimulation
Follicle to Oocyte Index (FOI)
Time Frame: 7 -20 days from initiation of ovarian stimulation
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
Total dose of rFSH
Time Frame: 7 -20 days from initiation of ovarian stimulation
7 -20 days from initiation of ovarian stimulation
Follicular Output Rate (FORT)
Time Frame: 7 -20 days from initiation of ovarian stimulation
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
Cycle cancelation rate
Time Frame: Until 15 days after the beginning of ovarian stimulation
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
Reason for cycle cancelation
Time Frame: Until 15 days after the beginning of ovarian stimulation
Until 15 days after the beginning of ovarian stimulation
Fertilization rate
Time Frame: One day after oocyte pick-up
One day after oocyte pick-up
Time of appearance of the 2nd polar body (tPB2)
Time Frame: One day after oocyte pick-up
One day after oocyte pick-up
Time of pronuclei appearance (tPNa)
Time Frame: One day after oocyte pick-up
One day after oocyte pick-up
Evaluation of both pronuclei (PN)
Time Frame: One day after oocyte pick-up
One day after oocyte pick-up
Time of pronuclei disappearance (tPNf)
Time Frame: Day 2 after insemination
Day 2 after insemination
Time of division from 2 to 8 cells (t2, t3, t4, t5, t6, t7, t8)
Time Frame: Until Day 2 Day 3 after insemination
Until Day 2 Day 3 after insemination
Time of compactation (tSC)
Time Frame: Until Day 3 Day 6 after insemination
Until Day 3 Day 6 after insemination
Time of morula (tM)
Time Frame: Until Day 3 Day 6 after insemination
Until Day 3 Day 6 after insemination
Time of cavitation (tSB)
Time Frame: Until 5, 6 or 7 days after insemination
Until 5, 6 or 7 days after insemination
Time of full blastulation (tB)
Time Frame: Until 5, 6 or 7 days after insemination
Until 5, 6 or 7 days after insemination
Time of expanded blastocyst (tEB)
Time Frame: Until 5, 6 or 7 days after insemination
Until 5, 6 or 7 days after insemination
Time of hatched blastocyst (tHB)
Time Frame: Until 5, 6 or 7 days after insemination
Until 5, 6 or 7 days after insemination
Time of embryo discarding (tDead)
Time Frame: Until 7 days after insemination
Until 7 days after insemination
Total number of embryos
Time Frame: Until 5, 6 or 7 days after insemination
Until 5, 6 or 7 days after insemination
Blastocyst formation rate
Time Frame: Until 5, 6 or 7 days after insemination
Until 5, 6 or 7 days after insemination
Number of embryos cryopreserved
Time Frame: Until 5, 6 or 7 days after insemination
Until 5, 6 or 7 days after insemination
Embryo stage (D5, D6, D7)
Time Frame: Until 5, 6 or 7 days after insemination
Until 5, 6 or 7 days after insemination
Clinical pregnancy rate
Time Frame: 5 to 6 weeks after oocyte pick-up
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
Ongoing pregnancy rate
Time Frame: 8 to 10 weeks after oocyte pick-up
8 to 10 weeks after oocyte pick-up

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Miscarriages
Time Frame: before completion of 12 weeks of gestation
any spontaneous abortion that occurred after confirmation of clinical pregnancy
before completion of 12 weeks of gestation
Incidence of adverse events and serious adverse events
Time Frame: Until 15 days after the end of ovarian stimulation
Until 15 days after the end of ovarian stimulation
Ovarian hyperstimulation syndrome (OHSS) (percent)
Time Frame: Until 15 days after the end of ovarian stimulation
Number of subjects with OHSS during the ovarian stimulation period and their severity
Until 15 days after the end of ovarian stimulation

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fundación Santiago Dexeus Font

Investigators

  • Study Chair: Nikolaos P Polyzos, MD PhD, Hospital Universitari Dexeus
  • Principal Investigator: Ana Neves, MD, Hospital Universitari Dexeus

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 23, 2021

Primary Completion (Actual)

March 11, 2026

Study Completion (Actual)

March 11, 2026

Study Registration Dates

First Submitted

July 5, 2021

First Submitted That Met QC Criteria

July 19, 2021

First Posted (Actual)

July 30, 2021

Study Record Updates

Last Update Posted (Actual)

April 14, 2026

Last Update Submitted That Met QC Criteria

April 13, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • FSD-IEQ-2021-03
  • 2021-000941-42 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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