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

NCT05638529 | Unknown Phase 4

• 1 other identifier: 17-0302-A
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Ovarian Hyperstimulation Syndrome; Infertility, Female

Keywords

oocyte Maturity; Dual Trigger; Infertility, Female

Outcome Measures

Primary Outcomes (1)

• Total number of Day 5 embryos

  Total number of "good quality" Day 5 embryos available for cryopreservation.

  after 5 days of oocyte fertilization

Secondary Outcomes (11)

• 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

  3-5 days after the egg retrieval

• Total number of Day 3 embryos.

  3 days after the fertilization of oocyte

Study Arms (2)

Treatment Arm- Group A

EXPERIMENTAL

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

Control Arm- Group B

PLACEBO COMPARATOR

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

Interventions

Pregnyl (1,500) IU DRUG

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.

Also known as: Hcg

Treatment Arm- Group A

1.5 mL of normal saline DRUG

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.

Also known as: Normal Saline

Control Arm- Group B

Eligibility Criteria

• Age: 18 Years - 40 Years
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Mount Sinai Hospital, Canada: lead

Study Sites (1)

Mount Sinai Hospital, Fertility Clinic

Toronto, Ontario, M5G1X6, Canada

Location

Related Publications (28)

• Corbett S, Shmorgun D, Claman P; REPRODUCTIVE ENDOCRINOLOGY INFERTILITY COMMITTEE; SPECIAL CONTRIBUTOR. The prevention of ovarian hyperstimulation syndrome. J Obstet Gynaecol Can. 2014 Nov;36(11):1024-1033. doi: 10.1016/S1701-2163(15)30417-5. English, French.

  PMID: 25574681 BACKGROUND

• Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004 Jan;81(1):19-25. doi: 10.1016/j.fertnstert.2003.10.004.

  PMID: 14711538 BACKGROUND

• Ferraretti AP, Gianaroli L, Magli C, Fortini D, Selman HA, Feliciani E. Elective cryopreservation of all pronucleate embryos in women at risk of ovarian hyperstimulation syndrome: efficiency and safety. Hum Reprod. 1999 Jun;14(6):1457-60. doi: 10.1093/humrep/14.6.1457.

  PMID: 10357958 BACKGROUND

• Galindo A, Bodri D, Guillen JJ, Colodron M, Vernaeve V, Coll O. Triggering with HCG or GnRH agonist in GnRH antagonist treated oocyte donation cycles: a randomised clinical trial. Gynecol Endocrinol. 2009 Jan;25(1):60-6. doi: 10.1080/09513590802404013.

  PMID: 19165664 BACKGROUND

• Griffin D, Benadiva C, Kummer N, Budinetz T, Nulsen J, Engmann L. Dual trigger of oocyte maturation with gonadotropin-releasing hormone agonist and low-dose human chorionic gonadotropin to optimize live birth rates in high responders. Fertil Steril. 2012 Jun;97(6):1316-20. doi: 10.1016/j.fertnstert.2012.03.015. Epub 2012 Apr 3.

  PMID: 22480822 BACKGROUND

• Huang CY, Shieh ML, Li HY. The benefit of individualized low-dose hCG support for high responders in GnRHa-triggered IVF/ICSI cycles. J Chin Med Assoc. 2016 Jul;79(7):387-93. doi: 10.1016/j.jcma.2016.02.006. Epub 2016 May 1.

  PMID: 27147462 BACKGROUND

• Lin H, Wang W, Li Y, Chen X, Yang D, Zhang Q. Triggering final oocyte maturation with reduced doses of hCG in IVF/ICSI: a prospective, randomized and controlled study. Eur J Obstet Gynecol Reprod Biol. 2011 Nov;159(1):143-7. doi: 10.1016/j.ejogrb.2011.07.009. Epub 2011 Aug 6.

  PMID: 21824709 BACKGROUND

• Ludwig M, Doody KJ, Doody KM. Use of recombinant human chorionic gonadotropin in ovulation induction. Fertil Steril. 2003 May;79(5):1051-9. doi: 10.1016/s0015-0282(03)00173-0.

  PMID: 12738494 BACKGROUND

• McClure N, Healy DL, Rogers PA, Sullivan J, Beaton L, Haning RV Jr, Connolly DT, Robertson DM. Vascular endothelial growth factor as capillary permeability agent in ovarian hyperstimulation syndrome. Lancet. 1994 Jul 23;344(8917):235-6. doi: 10.1016/s0140-6736(94)93001-5.

  PMID: 7913160 BACKGROUND

• Melo M, Busso CE, Bellver J, Alama P, Garrido N, Meseguer M, Pellicer A, Remohi J. GnRH agonist versus recombinant HCG in an oocyte donation programme: a randomized, prospective, controlled, assessor-blind study. Reprod Biomed Online. 2009 Oct;19(4):486-92. doi: 10.1016/j.rbmo.2009.06.001.

  PMID: 19909588 BACKGROUND

• Nargund G, Hutchison L, Scaramuzzi R, Campbell S. Low-dose HCG is useful in preventing OHSS in high-risk women without adversely affecting the outcome of IVF cycles. Reprod Biomed Online. 2007 Jun;14(6):682-5. doi: 10.1016/s1472-6483(10)60668-2.

  PMID: 17579978 BACKGROUND

• Neulen J, Yan Z, Raczek S, Weindel K, Keck C, Weich HA, Marme D, Breckwoldt M. Human chorionic gonadotropin-dependent expression of vascular endothelial growth factor/vascular permeability factor in human granulosa cells: importance in ovarian hyperstimulation syndrome. J Clin Endocrinol Metab. 1995 Jun;80(6):1967-71. doi: 10.1210/jcem.80.6.7775647.

  PMID: 7775647 BACKGROUND

• O'Neill KE, Senapati S, Maina I, Gracia C, Dokras A. GnRH agonist with low-dose hCG (dual trigger) is associated with higher risk of severe ovarian hyperstimulation syndrome compared to GnRH agonist alone. J Assist Reprod Genet. 2016 Sep;33(9):1175-84. doi: 10.1007/s10815-016-0755-8. Epub 2016 Jun 27.

  PMID: 27349252 BACKGROUND

• Oktay K, Turkcuoglu I, Rodriguez-Wallberg KA. GnRH agonist trigger for women with breast cancer undergoing fertility preservation by aromatase inhibitor/FSH stimulation. Reprod Biomed Online. 2010 Jun;20(6):783-8. doi: 10.1016/j.rbmo.2010.03.004. Epub 2010 Mar 6.

  PMID: 20382080 BACKGROUND

• Orvieto R, Rabinson J, Meltzer S, Zohav E, Anteby E, Homburg R. Substituting HCG with GnRH agonist to trigger final follicular maturation--a retrospective comparison of three different ovarian stimulation protocols. Reprod Biomed Online. 2006 Aug;13(2):198-201. doi: 10.1016/s1472-6483(10)60615-3.

  PMID: 16895632 BACKGROUND

• Papanikolaou EG, Pozzobon C, Kolibianakis EM, Camus M, Tournaye H, Fatemi HM, Van Steirteghem A, Devroey P. Incidence and prediction of ovarian hyperstimulation syndrome in women undergoing gonadotropin-releasing hormone antagonist in vitro fertilization cycles. Fertil Steril. 2006 Jan;85(1):112-20. doi: 10.1016/j.fertnstert.2005.07.1292.

  PMID: 16412740 BACKGROUND

• Pellicer A, Albert C, Mercader A, Bonilla-Musoles F, Remohi J, Simon C. The pathogenesis of ovarian hyperstimulation syndrome: in vivo studies investigating the role of interleukin-1beta, interleukin-6, and vascular endothelial growth factor. Fertil Steril. 1999 Mar;71(3):482-9. doi: 10.1016/s0015-0282(98)00484-1.

  PMID: 10065786 BACKGROUND

• Practice Committee of the American Society for Reproductive Medicine. Electronic address: ASRM@asrm.org; Practice Committee of the American Society for Reproductive Medicine. Prevention and treatment of moderate and severe ovarian hyperstimulation syndrome: a guideline. Fertil Steril. 2016 Dec;106(7):1634-1647. doi: 10.1016/j.fertnstert.2016.08.048. Epub 2016 Sep 24.

  PMID: 27678032 BACKGROUND

• Revelli A, Carosso A, Grassi G, Gennarelli G, Canosa S, Benedetto C. Empty follicle syndrome revisited: definition, incidence, aetiology, early diagnosis and treatment. Reprod Biomed Online. 2017 Aug;35(2):132-138. doi: 10.1016/j.rbmo.2017.04.012. Epub 2017 May 23.

  PMID: 28596003 BACKGROUND

• Schmidt DW, Maier DB, Nulsen JC, Benadiva CA. Reducing the dose of human chorionic gonadotropin in high responders does not affect the outcomes of in vitro fertilization. Fertil Steril. 2004 Oct;82(4):841-6. doi: 10.1016/j.fertnstert.2004.03.055.

  PMID: 15482757 BACKGROUND

• Shaker AG, Zosmer A, Dean N, Bekir JS, Jacobs HS, Tan SL. Comparison of intravenous albumin and transfer of fresh embryos with cryopreservation of all embryos for subsequent transfer in prevention of ovarian hyperstimulation syndrome. Fertil Steril. 1996 May;65(5):992-6. doi: 10.1016/s0015-0282(16)58275-2.

  PMID: 8612863 BACKGROUND

• Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Hudson C. Comparison of "triggers" using leuprolide acetate alone or in combination with low-dose human chorionic gonadotropin. Fertil Steril. 2011 Jun 30;95(8):2715-7. doi: 10.1016/j.fertnstert.2011.03.109. Epub 2011 May 7.

  PMID: 21550042 BACKGROUND

• Youssef MA, Van der Veen F, Al-Inany HG, Mochtar MH, Griesinger G, Nagi Mohesen M, Aboulfoutouh I, van Wely M. Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist-assisted reproductive technology. Cochrane Database Syst Rev. 2014 Oct 31;2014(10):CD008046. doi: 10.1002/14651858.CD008046.pub4.

  PMID: 25358904 BACKGROUND

• Sismanoglu A, Tekin HI, Erden HF, Ciray NH, Ulug U, Bahceci M. Ovulation triggering with GnRH agonist vs. hCG in the same egg donor population undergoing donor oocyte cycles with GnRH antagonist: a prospective randomized cross-over trial. J Assist Reprod Genet. 2009 May;26(5):251-6. doi: 10.1007/s10815-009-9326-6. Epub 2009 Jul 23.

  PMID: 19629674 BACKGROUND

• Werner, M. D., Forman, E. J., Hong, K. H., Franasiak, J. M., Neal, S. A., & Scott, R. T. (2014). Dual trigger with GnRH agonist (GnRHa) and varying doses of hCG increases the blastulation rate amongst high responders. Fertility and Sterility, 102(3), e220

  BACKGROUND

• Angelo, D. A., & Nn, A. (2012). Embryo freezing for preventing ovarian hyperstimulation syndrome (Review) SUMMARY OF FINDINGS FOR THE MAIN COMPARISON, (3).

  BACKGROUND

• Shaltout, A., Eid, M., & Shohayeb, A. (2006). Does triggering ovulation by 5000 IU of uhCG affect ICSI outcome? Middle East Fertility Society Journal, 11: 99-103.

  BACKGROUND

• Gardner DK, Schoolcraft WB. In vitro culture of human blastocyst. In: Janson R, Mortimer D, editors. Towards Reproductive Certainty: Infertility and Genetics Beyond 1999. Carnforth: Parthenon Press; 1999. p. 378-88.

  BACKGROUND

MeSH Terms

Conditions

Ovarian Hyperstimulation Syndrome; Infertility, Female

Interventions

Chorionic Gonadotropin; Thyrotropin Alfa; Saline Solution

Condition Hierarchy (Ancestors)

Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Gonadal Disorders; Endocrine System Diseases; Infertility

Intervention Hierarchy (Ancestors)

Gonadotropins; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Placental Hormones; Peptides; Amino Acids, Peptides, and Proteins; Pregnancy Proteins; Proteins; Thyrotropin; Pituitary Hormones, Anterior; Pituitary Hormones; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Miguel Russo, MD

  Mount Sinai Hospital, Canada

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Physician

Study Record Dates

• First Submitted: November 23, 2022
• First Posted: December 6, 2022
• Study Start: May 1, 2019
• Primary Completion: December 31, 2023
• Study Completion: December 31, 2023
• Last Updated: July 3, 2023

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)