Gonadotropin Releasing Hormone Agonist (GnRHa) Versus Estrogen and Progesterone for Luteal Support in High Responders

NCT04797338 | Unknown Phase 4 FDA Drug

• 1 other identifier: 0245-17-ASF
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

Gonadotropin Releasing Hormone agonist (GnRHa) triggering is used as an alternative to human chorionic gonadotropin (hCG) in GnRH antagonist protocol to eliminate the risk of ovarian hyperstimulation syndrome (OHSS). However, its main disadvantage is a significantly lower pregnancy rate, hypothesized to result from a process called "luteolysis" (demise of the corpora lutea). In order to preserve a high pregnancy rates, several luteal support regimens were investigated, including an intensive estrogen and progesterone supplementation and a daily GnRHa treatment. However, no study, so far, compared the efficacy of these two regimens. Our aim is to compare the efficacy of GnRHa versus estrogen and progesterone supplementation for luteal phase support in high responders following GnRHa triggering.

Conditions

Pregnancy Early; Miscarriage; Ovarian Hyperstimulation Syndrome

Outcome Measures

Primary Outcomes (2)

• clinical pregnancy rate

  an ultrasound visualization of one or more gestational sacs

  3 weeks after positive serum bHCG results

• Clinical pregnancy rate with fetal heart beat

  clinical pregnancy with a demonstration of fetal heart by ultrasound visualization

  3 weeks after positive serum bHCG results

Secondary Outcomes (2)

• Miscarriage rate

  from the demonstration of a clinical pregnancy (3 weeks after positive serum bHCG results) up to 22 weeks

• Ovarian hyperstimulation syndrome (OHSS) rate

  up to 12 days post embryo transfer

Study Arms (2)

GnRHa treatment based luteal support

ACTIVE COMPARATOR

Patients will initiate intranasal treatment with Nafarelin inhaler: 200 micrograms twice daily (a total of 400 micrograms/d; Synarel, Pfizer) on the evening after oocyte retrieval which will be continued up to the bHCG blood test, 12 days post embryo transfer. In cases with positive serum hCG results, the treatment will be stopped.

Drug: Synarel, 0.2 Mg/Inh Nasal Spray

Estrogen and progesterone supplementation

ACTIVE COMPARATOR

Patients will start treatment with a combination of oral estrogen (Estrofem or Progynova 4 mg twice daily), vaginal progesterone (vaginal Utrogestan 200mg or Endometrin 100 mg three times daily) and intramuscular injection of progesterone retard 250 mg once every five days. The treatment will start at the day of the oocyte retrieval up to the bHCG blood test, 12 days post embryo transfer. In cases with positive serum hCG results, the treatment will be continued up to 9+0 weeks of pregnancy.

Drug: Estrofem; Drug: Utrogestan; Drug: Hydroxyprogesterone Caproate

Interventions

Synarel, 0.2 Mg/Inh Nasal Spray DRUG

Intranasal treatment with Nafarelin inhaler: 200 micrograms twice daily (a total of 400 micrograms/d; Synarel, Pfizer) on the evening after oocyte retrieval, which will be continued up to the bHCG blood test, 12 days post embryo transfer. In cases with positive serum bHCG results, the treatment will be stopped.

Also known as: Nafarelin

GnRHa treatment based luteal support

Estrofem DRUG

A combination of oral estrogen (Estrofem or Progynova 4 mg twice daily), vaginal progesterone (vaginal Utrogestan 200mg or Endometrin 100 mg three times daily) and intramuscular injection of Hydroxyprogesterone Caproate 250 mg once every five days. The treatment will start at the day of the oocyte retrieval up to the bHCG blood test, 12 days post embryo transfer. In cases with positive serum bHCG results, the treatment will be continued up to 9+0 weeks of pregnancy.

Also known as: Progynova

Estrogen and progesterone supplementation

Utrogestan DRUG

A combination of oral estrogen (Estrofem or Progynova 4 mg twice daily), vaginal progesterone (vaginal Utrogestan 200mg or Endometrin 100 mg three times daily) and intramuscular injection of Hydroxyprogesterone Caproate 250 mg once every five days. The treatment will start at the day of the oocyte retrieval up to the bHCG blood test, 12 days post embryo transfer. In cases with positive serum bHCG results, the treatment will be continued up to 9+0 weeks of pregnancy.

Also known as: Endometrin

Estrogen and progesterone supplementation

Hydroxyprogesterone Caproate DRUG

A combination of oral estrogen (Estrofem or Progynova 4 mg twice daily), vaginal progesterone (vaginal Utrogestan 200mg or Endometrin 100 mg three times daily) and intramuscular injection of Hydroxyprogesterone Caproate 250 mg once every five days. The treatment will start at the day of the oocyte retrieval up to the bHCG blood test, 12 days post embryo transfer. In cases with positive serum bHCG results, the treatment will be continued up to 9+0 weeks of pregnancy.

Also known as: Proluton Depot

Estrogen and progesterone supplementation

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• High responder patients, defined as either reaching a serum estradiol levels of ≥ 3500 pg/ml on the day of trigger or having ≥ 15 oocytes retrieved.
• Increased risk for OHSS (PCOS, previous history of OHSS, high antral follicle count (AFC) etc.).

You may not qualify if:

• Repeated implantation failure (3 or more previous failed embryo transfer cycles while transferring good quality embryos).
• Oocyte donation, fertility preservation or Freeze all (freezing all the embryos) cycles.
• Moderate to severe endometriosis
• An evidence of hydrosalpinx

Sponsors & Collaborators

• Assaf-Harofeh Medical Center: lead

Study Sites (1)

Shamir Medical center

Be’er Ya‘aqov, Israel

RECRUITING

Related Publications (19)

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• Damewood MD, Shen W, Zacur HA, Schlaff WD, Rock JA, Wallach EE. Disappearance of exogenously administered human chorionic gonadotropin. Fertil Steril. 1989 Sep;52(3):398-400. doi: 10.1016/s0015-0282(16)60906-8.

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• Leth-Moller K, Hammer Jagd S, Humaidan P. The Luteal Phase after GnRHa Trigger-Understanding An Enigma. Int J Fertil Steril. 2014 Oct;8(3):227-34. Epub 2014 Nov 1.

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  PMID: 7720926 BACKGROUND

• Balasch J, Martinez F, Jove I, Cabre L, Coroleu B, Barri PN, Vanrell JA. Inadvertent gonadotrophin-releasing hormone agonist (GnRHa) administration in the luteal phase may improve fecundity in in-vitro fertilization patients. Hum Reprod. 1993 Jul;8(7):1148-51. doi: 10.1093/oxfordjournals.humrep.a138210.

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  PMID: 8243703 BACKGROUND

• Weissman A, Shoham Z. Favourable pregnancy outcome after administration of a long-acting gonadotrophin-releasing hormone agonist in the mid-luteal phase. Hum Reprod. 1993 Mar;8(3):496-7. doi: 10.1093/oxfordjournals.humrep.a138079.

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• Tesarik J, Hazout A, Mendoza-Tesarik R, Mendoza N, Mendoza C. Beneficial effect of luteal-phase GnRH agonist administration on embryo implantation after ICSI in both GnRH agonist- and antagonist-treated ovarian stimulation cycles. Hum Reprod. 2006 Oct;21(10):2572-9. doi: 10.1093/humrep/del173. Epub 2006 Aug 22.

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• Pirard C, Loumaye E, Laurent P, Wyns C. Contribution to More Patient-Friendly ART Treatment: Efficacy of Continuous Low-Dose GnRH Agonist as the Only Luteal Support-Results of a Prospective, Randomized, Comparative Study. Int J Endocrinol. 2015;2015:727569. doi: 10.1155/2015/727569. Epub 2015 Apr 5.

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• Bar-Hava I, Mizrachi Y, Karfunkel-Doron D, Omer Y, Sheena L, Carmon N, Ben-David G. Intranasal gonadotropin-releasing hormone agonist (GnRHa) for luteal-phase support following GnRHa triggering, a novel approach to avoid ovarian hyperstimulation syndrome in high responders. Fertil Steril. 2016 Aug;106(2):330-3. doi: 10.1016/j.fertnstert.2016.04.004. Epub 2016 Apr 22.

  PMID: 27114332 BACKGROUND

MeSH Terms

Conditions

Abortion, Spontaneous; Ovarian Hyperstimulation Syndrome

Interventions

Nafarelin; estradiol, estriol drug combination; Estradiol; Utrogestan; Progesterone; 17 alpha-Hydroxyprogesterone Caproate

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Gonadotropin-Releasing Hormone; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Pregnenediones; Pregnenes; Pregnanes; Corpus Luteum Hormones; Progesterone Congeners; 17-alpha-Hydroxyprogesterone; Hydroxyprogesterones

Study Officials

• Michal Youngster, MD

  Assaf-Harofeh Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Michal Youngster, MD

CONTACT

972-506430111; michalyo@gmail.co.il

Lilach Marom Haham, MD

CONTACT

4167160958; mh.lilach@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: principal investigator

Model Details: A randomization list will be generated by a computer by 1:1 ratio. Sealed envelopes containing treatment allocation instructions will be attached to the consent forms. At the day of triggering for final oocyte maturation, patients will sign an informed consent and will be allocated to one of the study arms according to the instructions in the envelop attached to the consent form.

Study Record Dates

• First Submitted: March 3, 2021
• First Posted: March 15, 2021
• Study Start: December 29, 2017
• Primary Completion: September 30, 2021
• Study Completion: September 30, 2021
• Last Updated: April 1, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

IL (1)