INTEnsity of ovariaN Stimulation and Embryo Quality

Study Overview
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Brief Summary
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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).

Detailed Description
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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).

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

Conditions
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Infertility

Intervention / Treatment
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* Drug: Ovarian Stimulation with CC+rFSH
* Drug: Ovarian Stimulation with rFSH


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: Clomiphene Citrate (CC) + rFSH<br>Ovarian Stimulation with CC+rFSH | Drug: Ovarian Stimulation with CC+rFSH<br>* : 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®)<br>|
| Active Comparator: rFSH<br>Ovarian Stimulation with rFSH | Drug: Ovarian Stimulation with rFSH<br>* 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®)<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

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