Effect of GnRH Agonist vs GnRH Antagonist on IVF/ICSI Outcomes.

Sponsor

Damascus University (Other)

Overall Status

Recruiting

CT.gov ID

NCT04724343

Collaborator

(none)

Enrollment

Location

Arms

20.3

Anticipated Duration (Months)

2.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The aim of this prospective, non-randomised, open-label, clinical trial is to compare the effects of two pituitary suppression regimens; GnRH Agonist-Long Protocol and GnRH Antagonist-Flexible Protocol on clinical and embryological IVF/ICSI outcomes, and on the follicular fluid levels of Placental Growth Factor (PlGF); which is known for his pivotal role in the regulation of ovulation, embryo development, and implantation.

Condition or Disease	Intervention/Treatment	Phase
In Vitro Fertilization Intracytoplasmic Sperm Injection Infertility	Drug: Triptorelin acetate Drug: Cetrorelix Drug: recombinant-FSH or recombinant-FSH + human Menopausal Gonadotropin Drug: Human Chorionic Gonadotropin (hCG)	Phase 4

Study Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Effect of GnRH Agonist (Long Protocol) vs GnRH Antagonist (Flexible Protocol) on IVF/ICSI Outcomes.

Actual Study Start Date :

Dec 22, 2019

Anticipated Primary Completion Date :

Aug 1, 2021

Anticipated Study Completion Date :

Sep 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Agonist Group (Long protocol): The pituitary down-regulation in this group will be carried out using 0.05-0.1 mg of Triptorelin acetate subcutaneously (SC) once daily from the mid-luteal phase (day 21) of the menstrual cycle until the ovulation triggering day. When the suppressive effect is obtained, ovarian stimulation will commence with recombinant Follicle-Stimulating Hormone (r-FSH) or r-FSH + human Menopausal Gonadotropin (hMG) and the dose will be adjusted according to the ovarian response. Ovulation will be triggered by the administration of 10,000 IU of human Chorionic Gonadotropin (hCG) when at least three follicles become more than 16-17 mm. After 35±2 hours of ovulation triggering, the oocytes will be retrieved by transvaginal ultrasound-guided follicle aspiration. Then they will be prepared to undergo an Intracytoplasmic Sperm Injection (ICSI).	Drug: Triptorelin acetate 0.05-0.1 mg subcutaneously (SC) once daily from the mid-luteal phase (day 21) of the cycle until the day of ovulation triggering. Drug: recombinant-FSH or recombinant-FSH + human Menopausal Gonadotropin Dosage adjustment according to the ovarian response. Drug: Human Chorionic Gonadotropin (hCG) Ovulation will be triggered by the administration of 10,000 IU of Human Chorionic Gonadotropin (hCG) when at least three follicles become more than 16-17 mm.
Experimental: Antagonist Group (Flexible protocol): The ovarian stimulation in this group will be started with recombinant Follicle-Stimulating Hormone (r-FSH) or r-FSH + human Menopausal Gonadotropin (hMG) on the third day of the menstrual cycle and the dose will be adjusted according to the ovarian response. Initiation of 0.25 mg of GnRH antagonist; Cetrorelix; will take place after detecting a leading follicle diameter ≥ 14 mm. GnRH antagonist administration will be continued till the day of ovulation triggering, which will be accomplished by given 10,000 IU of human Chorionic Gonadotropin (hCG) when at least three follicles become more than 16-17 mm. After 35±2 hours of ovulation triggering, the oocytes will be retrieved by transvaginal ultrasound-guided follicle aspiration. Then they will be prepared to undergo an Intracytoplasmic Sperm Injection (ICSI).	Drug: Cetrorelix 0.25 mg subcutaneously (SC) once daily starting from the day detecting a leading follicle diameter ≥ 14 mm until the day of ovulation triggering. Drug: recombinant-FSH or recombinant-FSH + human Menopausal Gonadotropin Dosage adjustment according to the ovarian response. Drug: Human Chorionic Gonadotropin (hCG) Ovulation will be triggered by the administration of 10,000 IU of Human Chorionic Gonadotropin (hCG) when at least three follicles become more than 16-17 mm.

Arm

Intervention/Treatment

Active Comparator: Agonist Group (Long protocol):

The pituitary down-regulation in this group will be carried out using 0.05-0.1 mg of Triptorelin acetate subcutaneously (SC) once daily from the mid-luteal phase (day 21) of the menstrual cycle until the ovulation triggering day. When the suppressive effect is obtained, ovarian stimulation will commence with recombinant Follicle-Stimulating Hormone (r-FSH) or r-FSH + human Menopausal Gonadotropin (hMG) and the dose will be adjusted according to the ovarian response. Ovulation will be triggered by the administration of 10,000 IU of human Chorionic Gonadotropin (hCG) when at least three follicles become more than 16-17 mm. After 35±2 hours of ovulation triggering, the oocytes will be retrieved by transvaginal ultrasound-guided follicle aspiration. Then they will be prepared to undergo an Intracytoplasmic Sperm Injection (ICSI).

Drug: Triptorelin acetate

0.05-0.1 mg subcutaneously (SC) once daily from the mid-luteal phase (day 21) of the cycle until the day of ovulation triggering.

Drug: recombinant-FSH or recombinant-FSH + human Menopausal Gonadotropin

Dosage adjustment according to the ovarian response.

Drug: Human Chorionic Gonadotropin (hCG)

Ovulation will be triggered by the administration of 10,000 IU of Human Chorionic Gonadotropin (hCG) when at least three follicles become more than 16-17 mm.

Experimental: Antagonist Group (Flexible protocol):

The ovarian stimulation in this group will be started with recombinant Follicle-Stimulating Hormone (r-FSH) or r-FSH + human Menopausal Gonadotropin (hMG) on the third day of the menstrual cycle and the dose will be adjusted according to the ovarian response. Initiation of 0.25 mg of GnRH antagonist; Cetrorelix; will take place after detecting a leading follicle diameter ≥ 14 mm. GnRH antagonist administration will be continued till the day of ovulation triggering, which will be accomplished by given 10,000 IU of human Chorionic Gonadotropin (hCG) when at least three follicles become more than 16-17 mm. After 35±2 hours of ovulation triggering, the oocytes will be retrieved by transvaginal ultrasound-guided follicle aspiration. Then they will be prepared to undergo an Intracytoplasmic Sperm Injection (ICSI).

Drug: Cetrorelix

0.25 mg subcutaneously (SC) once daily starting from the day detecting a leading follicle diameter ≥ 14 mm until the day of ovulation triggering.

Drug: recombinant-FSH or recombinant-FSH + human Menopausal Gonadotropin

Dosage adjustment according to the ovarian response.

Drug: Human Chorionic Gonadotropin (hCG)

Ovulation will be triggered by the administration of 10,000 IU of Human Chorionic Gonadotropin (hCG) when at least three follicles become more than 16-17 mm.

Outcome Measures

Primary Outcome Measures

Follicular fluid Placental Growth Factor (PlGF) Concentrations: [Immediately after oocyte retrieval (35±2 hours after hCG administration)]
Follicular fluid samples will be obtained on the day of oocyte retrieval, then they will be centrifuged to eliminate cellular elements and debris. After that, the supernatants will be frozen at -80 until assayed using an Eliza kit.

Secondary Outcome Measures

Number of oocytes retrieved: [Immediately after oocyte retrieval (35±2 hours after hCG administration)]
The oocytes will be retrieved by transvaginal ultrasound-guided follicle aspiration 35±2 hours after hCG administration.
Number of Metaphase II Oocytes (MII): [Within two hours after oocyte retrieval]
The oocyte maturity will be assessed using Nikon SMZ1500 stereoscope.
Maturation Rate%: [Within two hours after oocyte retrieval]
Maturation Rate is calculated by dividing the number of mature (MII) oocytes by the number of retrieved oocytes.
Fertilization Rate%: [16-18 hours after microinjection]
Fertilization Rate is calculated by dividing the number of obtained zygote (2PN) by the number of injected oocytes.
Cleavage Rate%: [Day 2 after microinjection]
Cleavage rate is calculated by dividing the number of cleavaged embryos by the number of zygotes (2PN).
Embryo Quality: [Day of transfer (2 or 3 days after microinjection)]
Embryos are assessed using Nikon SMZ1500 stereoscope based on ESHRE criteria (2011).
High Quality Embryos rate%: [Day of transfer (2 or 3 days after microinjection)]
High Quality Embryos rate is calculated by dividing the number of high quality embryos (Grade I) by the total number of cleavaged embryos.
Biochemical Pregnancy Rate% (Per Embryo Transfer): [2 weeks after embryo transfer]
Biochemical pregnancy is defined as a positive serum beta-hCG pregnancy test after 2 weeks of embryo transfer. The biochemical pregnancy rate is calculated by dividing the number of women who are biochemically pregnant by the number of women who have at least 1 embryo transferred.
Clinical Pregnancy Rate% (Per Embryo Transfer): [3-4 weeks after embryo transfer]
Clinical pregnancy is defined as the presence of a gestational sac on ultrasound after 3-4 weeks of embryo transfer. The clinical pregnancy rate is calculated as by dividing the number of women who are clinically pregnant divided by the number of women who have at least 1 embryo transferred.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 39 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Women undergoing IVF/ICSI.
Age: 18-39 years.
Both ovaries present.

Exclusion Criteria:

Age ≥ 40 years.
History of three or more previous IVF failures.
Patients with hormonal disorders like hyperprolactinemia, thyroid disorders.
Patients with Polycystic ovary syndrome.
Patients who previously undergo Unilateral Oophorectomy.
Patients with chronic diseases: diabetes mellitus, cardiovascular diseases, liver diseases, kidney diseases.
Patients with diseases may affect IVF outcomes: Endometriosis, uterine fibroids, Hydrosalpinx, Adenomyosis, autoimmune diseases,
Cancer.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Orient Hospital	Damascus		Syrian Arab Republic

Sponsors and Collaborators

Damascus University

Investigators

Principal Investigator: Sally Kadoura, B Pharm, MD, Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Damascus University, Damascus, Syria
Study Director: Abdul Hakim Nattouf, MD, PhD, Professor at Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Damascus University, Damascus, Syria
Study Director: Marwan Alhalabi, MD, PhD, Professor at Department of Embryology and Reproductive Medicine, Faculty of Medicine, Damascus University, Damascus, Syria.