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Ovarian Hyperstimulation SyndromePhase 4NCT05638529

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

A Phase 4 study testing Pregnyl (1,500) IU and 1.5 mL of normal saline in people with Ovarian Hyperstimulation Syndrome and Infertility, Female, run by Mount Sinai Hospital, Canada at 1 site in Canada.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 40 years, women only
What is being tested?
Pregnyl (1,500) IU and 1.5 mL of normal saline
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
80 participants
Where
1 siteCanada
Study dates
1 May 2019to 31 Dec 2023
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 18 to 40 years
  • Women only
  • No healthy volunteers
  • Adult

Who may be able to join

  • 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.

Who cannot join

  • 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.
Show all 11Show fewer
  • 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

Trial locations and contacts

1 site in 1 country.

Canada1 site
  • Mount Sinai Hospital, Fertility Clinic

    Toronto, Ontario, M5G1X6

Other trials in Canada

About this study

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

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.

Read the detailed description

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.

Being tested
Pregnyl (1,500) IU, 1.5 mL of normal saline
Keywords
oocyte Maturity, Dual Trigger, Infertility, Female
Medical subject headings
Ovarian Hyperstimulation Syndrome, Infertility, Female

What participants receive

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

  • Pregnyl (1,500) IUDrug

    Also called Hcg

    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.

  • 1.5 mL of normal salineDrug

    Also called Normal Saline

    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.

Study groups in NCT05638529
Study groupRoleWhat they receive
Treatment Arm- Group AExperimentalA subcutaneous injection of a GnRH agonist (Suprefact 0.5 mg) and a separate intramuscular injection of hCG (Pregnyl 1,500 IU).
Receives: Drug: Pregnyl (1,500) IU
Control Arm- Group BPlacebo comparatorA subcutaneous injection of a GnRH agonist (Suprefact 0.5 mg) and a separate intramuscular injection of normal saline (1.5 mL) (sham-placebo).
Receives: Drug: 1.5 mL of normal saline

What is being measured

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

  1. Total number of Day 5 embryos

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

    Measured: after 5 days of oocyte fertilization

Secondary outcomes (11)
  1. Total number of oocytes retrieved per cycle.

    Measured: within 1-2 days of oocyte retrieval

  2. Total number of mature oocytes (MII) retrieve per IVF/ICSI cycle.

    Measured: 2-3 days after oocyte retrieval

  3. Total number of fertilized zygotes.

    Measured: 3-5 days after the egg retrieval

  4. 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.

    Measured: 3-5 days after the egg retrieval

  5. Total number of Day 3 embryos.

    Measured: 3 days after the fertilization of oocyte

  6. Pregnancy Rate

    A serum b-hCG > 5 mIU/mL per transfer

    Measured: Upto 13 weeks after the embryo transfer

  7. Clinical pregnancy rate

    Number of gestational sac(s) with a positive fetal heart per transfer.

    Measured: Upto 13 weeks after the embryo transfer

  8. Implantation rate

    Number of gestational sac(s) divided by the number of embryo(s) transferred per FET.

    Measured: 3-4 weeks after implantation of embryos

  9. Miscarriage rate

    The number of spontaneous pregnancy losses before 20 weeks gestation divided by the number of clinical pregnancies

    Measured: Within 20 weeks from the date of the clinical intrauterine pregnancy confirmation ultrasount

  10. Live birth rate

    The number of live born neonates over 24 weeks gestation divided by the number of clinical pregnancies

    Measured: Per embryo(s) transferred during the study period and follow-up for up to 10 months after last transfer.]

  11. Incidence of moderate to critical OHSS

    Based on the classification criteria by Mathur et al. (2007).

    Measured: Upto 2 weeks from the date of intervention

Timeline

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

  1. First posted6 Dec 2022
  2. Study start1 May 2019
  3. Primary completion31 Dec 2023 (estimated)
  4. Study completion31 Dec 2023 (estimated)

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
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
80 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05638529
Sponsor's protocol ID
17-0302-A
Status last verified
Jun 2023
First submitted
23 Nov 2022
Last updated
3 Jul 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 25574681
  • 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.

    PubMed 14711538
  • 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.

    PubMed 10357958
  • 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.

    PubMed 19165664
  • 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.

    PubMed 22480822
  • 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.

    PubMed 27147462
  • 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.

    PubMed 21824709
  • 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.

    PubMed 12738494
  • 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.

    PubMed 7913160
  • 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.

    PubMed 19909588
  • 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.

    PubMed 17579978
  • 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.

    PubMed 7775647
  • 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.

    PubMed 27349252
  • 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.

    PubMed 20382080
  • 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.

    PubMed 16895632

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Pregnyl (1,500) IU and 1.5 mL of normal saline in people with Ovarian Hyperstimulation Syndrome and Infertility, Female, run by Mount Sinai Hospital, Canada at 1 site in Canada.

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 11 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: status not confirmed, as of the sponsor's last update on 3 Jul 2023. 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 Canada. 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. Some participants in this study may receive a placebo. 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?

Results are not available in the source record.

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?

Total number of Day 5 embryos (time frame: after 5 days of oocyte fertilization). 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 NCT05638529, which also lists 28 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 3 Jul 2023.

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