Dual Trigger in IVF Patients at High Risk of Ovarian Hyper Stimulation Syndrome

Study Overview
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Brief Summary
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The present study aims to evaluate whether the use of a dual trigger can improve IVF outcomes, compared to GnRH agonist (GnRH-a) alone, in patients at high risk of OHSS undergoing a freeze-all cycle. By examining freeze-all cycles with frozen embryo transfer(s) (FET) only, we eliminate the potential confounding issue of inadequate luteal support to the endometrium and focus primarily on the effect of a dual trigger on oocyte quality and embryo potential. To our best knowledge, there have been no randomized, controlled trials conducted to address this hypothesis.

Detailed Description
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While the use of GnRH-a trigger has nearly eliminated the risk of OHSS, several studies have shown that this strategy may be associated with poorer IVF outcomes after a fresh embryo transfer (Engmann et al., 2008; Galindo et al., 2009; Melo et al., 2017; Sismanoglu et al., 2009; Youssef et al., 2014). These findings may be partly explained by an inadequate LH surge, following a GnRH-a trigger, and raises two separate concerns. The first concern is whether an inadequate LH surge can have an detrimental effect on luteal support following a fresh embryo transfer. The corpus luteum requires constant LH stimulation, during implantation and early gestation, in order to optimize endometrial receptivity via the production of progesterone. The second concern is whether a suboptimal LH surge can reduce the number or quality of mature oocytes retrieved during a treatment cycle. Immature oocytes will not fertilize invitro and, therefore, can decrease a woman's overall success rate with IVF. Based on this second premise, another strategy was developed whereby a dual trigger, using a combination of a GnRH-a and a lower dose of hCG (1,500 IU), is used to help maximize the number of mature eggs retrieved during an IVF cycle without increasing the risk of OHSS. Two recent retrospective studies have evaluated the administration of a dual trigger with GnRH agonist in combination with low-dose hCG (1,000 IU), compared to GnRH agonist alone (O'Neill et al., 2016; Griffin et al., 2012). Both studies revealed a significant improvement in the number of mature oocytes retrieved between treatment and controls (Griffin et al., 2012). While these findings are promising, it is important to note that oocyte maturity does not equate to embryo potential. Therefore, whether the use of a dual trigger improves embryo development and competency, thus increasing a patient's success rate, remains to be determined.

Official Title
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Dual Versus Single Trigger in IVF Patients at High Risk of Ovarian Hyper Stimulation Syndrome: a Randomized, Double-blinded, Controlled Trial.

Conditions
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Ovarian Hyperstimulation Syndrome, Infertility, Female

Intervention / Treatment
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* Drug: Pregnyl (1,500) IU
* Drug: 1.5 mL of normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: They are between the ages of 18 and 40. They are undergoing IVF treatment with a GnRH antagonist protocol. During their current treatment cycle, they have at least one of the following risk factors for OHSS: Greater or equal to 13 follicles measuring at least 11 mm on the day of trigger. Serum estradiol levels greater or equal to 15,000 pmol/L on the day of trigger. Exclusion Criteria: They are using a GnRH agonist protocol (which is a contraindication to using a GnRH agonist trigger). They are planning on using a dual trigger (based on poor outcomes in a previous IVF cycle using a GnRH agonist trigger). They have a low ovarian reserve (AFC < 7 follicles or AMH < 10 pmol/L). They have had a previous failed GnRH agonist trigger. They have a known diagnosis of hypogonadotropic hypogonadism. They have had a previous adverse or allergic reaction to GnRH agonist in the past. They are using surgically retrieved sperm. They are undergoing treatment for fertility preservation (oncofertility patients). They have a history of recurrent implantation failure (defined as no clinical pregnancy after transfer of > 4 good-quality embryos). They have any congenital or acquire uterine anomalies distorting the uterine cavity. If serum estradiol levels are equal or exceed 28,000 pmol/L on the day of trigger

Ages Eligible for Study
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Minimum Age: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm- Group A<br>A subcutaneous injection of a GnRH agonist (Suprefact 0.5 mg) and a separate intramuscular injection of hCG (Pregnyl 1,500 IU). | Drug: Pregnyl (1,500) IU<br>* Patients will self-administer a subcutaneous injection of a GnRH agonist (Suprefact 0.5 mg) and a separate intramuscular injection of hCG (Pregnyl 1,500 IU) on their assigned trigger day.<br>* Other names: Hcg;|
| Placebo Comparator: Control Arm- Group B<br>A subcutaneous injection of a GnRH agonist (Suprefact 0.5 mg) and a separate intramuscular injection of normal saline (1.5 mL) (sham-placebo). | Drug: 1.5 mL of normal saline<br>* Patients will self-administer a subcutaneous injection of a GnRH agonist (Suprefact 0.5 mg) and a separate intramuscular injection of normal saline (1.5 mL - sham placebo) on their assigned trigger day.<br>* Other names: Normal Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total number of Day 5 embryos | Total number of good quality Day 5 embryos available for cryopreservation. | after 5 days of oocyte fertilization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total number of oocytes retrieved per cycle. |  | within 1-2 days of oocyte retrieval | 
| Total number of mature oocytes (MII) retrieve per IVF/ICSI cycle. |  | 2-3 days after oocyte retrieval | 
| Total number of fertilized zygotes. |  | 3-5 days after the egg retrieval | 
| Fertilization rate | Number of 2PN zygote(s) divided by the number of mature oocyte(s) fertilized per IVF/ICSI cycle OR Number of 2PN zygote(s) divided by the number of oocytes incubated with at least 10,000 sperm per IVF cycle. | 3-5 days after the egg retrieval | 
| Total number of Day 3 embryos. |  | 3 days after the fertilization of oocyte | 
| Pregnancy Rate | A serum b-hCG > 5 mIU/mL per transfer | Upto 13 weeks after the embryo transfer | 
| Clinical pregnancy rate | Number of gestational sac(s) with a positive fetal heart per transfer. | Upto 13 weeks after the embryo transfer | 
| Implantation rate | Number of gestational sac(s) divided by the number of embryo(s) transferred per FET. | 3-4 weeks after implantation of embryos | 
| Miscarriage rate | The number of spontaneous pregnancy losses before 20 weeks gestation divided by the number of clinical pregnancies | Within 20 weeks from the date of the clinical intrauterine pregnancy confirmation ultrasount | 
| Live birth rate | The number of live born neonates over 24 weeks gestation divided by the number of clinical pregnancies | Per embryo(s) transferred during the study period and follow-up for up to 10 months after last transfer.] | 
| Incidence of moderate to critical OHSS | Based on the classification criteria by Mathur et al. (2007). | Upto 2 weeks from the date of intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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oocyte Maturity, Dual Trigger, Infertility, Female