The Effect of Dual Trigger for Final Oocyte Maturation on IVF/ICSI Outcomes in Patients With Suboptimal Ovarian Response

• ClinicalTrials.gov Identifier: NCT04549649
• Recruitment Status: Recruiting
• First Posted: September 16, 2020
• Last Update Posted: December 16, 2020
• Sponsor: Royan Institute
• Information provided by (Responsible Party): Royan Institute

Study Description

Brief Summary:

Recently, in patients with a suboptimal ovarian response, a study of the role of adding a single dose of GnRH agonist to a standard dose of hCG to initiate final oocyte maturation has also been studied. Griffin et al. (2014) reported that in patients who had more than 25% immature oocytes in their previous IVF cycle, the use of dual stimulation could increase the number of mature oocytes. Since studies in this field are limited, the researchers decided to design a clinical trial to investigate the effect of adding a GnRH agonist to a standard dose of hCG to initiate final oocyte maturation in patients with a sub-optimal ovarian response.

Condition or disease	Intervention/treatment	Phase
Ovarian Stimulation; Reproductive Techniques, Assisted	Other: Dual triggering	Not Applicable

Detailed Description:

Ovulation stimulation will be performed in all patients with the Standard GnRH antagonist Protocol with E2 priming, with the antagonist protocol administered in all patients from the 20th cycle until the start of the next menstrual cycle with 4 mg of estradiol daily. Blood sampling (FSH, LH, and estradiol levels) will be performed on the second day of the menstrual cycle, just before gonadotropin stimulation. Ovarian stimulation will start from the second or third day of menstruation with a maximum dose of 225 units of rFSH (Gonal -F: Serono Laboratories Ltd, Geneva, Switzerland), and then if the follicle is observed, start with 13 injections of GnRH antagonist (Cetrotide®, 0.25 mg cetrorelix acetate, Serono, Inc)). From the seventh day of the cycle, the dose of rFSH will be determined according to the rate of ovarian response by vaginal ultrasonography two days in advance. If you see at least 2 follicles 18 mm in size or more, the antagonist will be injected. GnRH and gonadotropins (Gonal-F) will stop and (oocyte triggering) will be the final stimulation of oocyte maturation, at this time, the block randomization method will be designed to randomize allocation of patients into groups with blocks of size 4. Recently, in patients with a suboptimal ovarian response, a study of the role of adding a single dose of GnRH agonist to a standard dose of hCG to initiate final oocyte maturation has also been studied. Griffin et al. (2014) reported that in patients who had more than 25% immature oocytes in their previous IVF cycle, the use of dual stimulation could increase the number of mature oocytes. Since studies in this field are limited, the researchers decided to design a clinical trial to investigate the effect of adding a GnRH agonist to a standard dose of hCG to initiate final oocyte maturation in patients with a suboptimal ovarian response.

Controlled Ovulation stimulation (COS) will be performed in all patients with the Standard GnRH antagonist Protocol with E2 priming, with the antagonist protocol administered in all patients from the 20th cycle until the start of the next menstrual cycle with 4 mg of estradiol daily. Blood sampling (FSH, LH, and estradiol levels) will be performed on the second day of the menstrual cycle, just before gonadotropin stimulation. Ovarian stimulation will start from the second or third day of menstruation with a maximum dose of 225 units of rFSH (Gonal -F: Serono Laboratories Ltd, Geneva, Switzerland), and then if the follicle is observed, start with 13 injections of GnRH antagonist (Cetrotide®, 0.25 mg cetrorelix acetate, Serono, Inc)). From the seventh day of the cycle, the dose of rFSH will be determined according to the rate of ovarian response by vaginal ultrasonography two days in advance. If you see at least 2 follicles 18 mm in size or more, the antagonist will be injected. GnRH and gonadotropins (Gonal-F) will stop and (oocyte triggering) will be the final stimulation of oocyte maturation, at this time, the block randomization method will be designed to randomize allocation of patients into groups with blocks of size 4. The required number of blocks will be randomly selected according to sample size.

The final ovarian stimulation (oocyte triggering) will be performed in groups A and B as follows:

Group A (Experimental): 0.2 mg Triptorelin (Decapeptyl; Ferring GmbH) associated with two ampoules of Ovitrelle (Ovitrelle®, 250 μg/0.5 ml, Merck, Serono, Inc) will be administered subcutaneously simultaneously.

Group B (Control): Two ampoules of Ovitrelle® (Ovitrelle®, 250 μg/0.5 ml, Merck, Serono, Inc) will be injected subcutaneously.

The COS cycles with less than two follicles will be cancelled s. Ovum pick up is performed 32-34 hours after oocyte triggering, and subsequently intracytoplasmic sperm injection (ICSI) /in-vitro fertilization (IVF) will be done for all the patients.

The main outcome measures are the number of dominant follicles (≥13 mm) on the day of hCG trigger and the number of mature (MII) oocytes collected after conventional versus delayed-start ovarian stimulation protocol. Secondary outcome measures are including total number of oocytes retrieved, oocyte maturity rate (number of MII oocytes/total number of oocytes), oocyte yield (total number of oocytes retrieved/ antral follicle count [AFC]), mature oocyte yield (number of mature oocytes retrieved/AFC), total dosage of gonadotropin (recombinant FSH and/or highly purified hMG) needed, number of days needed for ovarian stimulation, quality of obtained embryos, fertilization rate (the proportion of total number of two-pronuclear [2PN] stage zygotes /per total injected MII oocytes), implantation rate (total number of observed gestational sac/ number of transferred embryos) and clinical pregnancy rate (presence of fetal heart beat by transvaginal ultrasound per embryo transfer).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Royan Institute for Reproductive Biomedicine
• Actual Study Start Date: November 1, 2019
• Estimated Primary Completion Date: September 30, 2021
• Estimated Study Completion Date: May 1, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Group A (Experimental oocyte triggering approach); 0.2 mg Triptorelin (Decapeptyl; Ferring GmbH) associated with two ampoules of Ovitrelle (Ovitrelle®, 250 μg/0.5 ml, Merck, Serono, Inc) will be administered subcutaneously simultaneously for final oocyte triggering.	Other: Dual triggering; Adding GnRH agonist (0.2 mg Triptorelin (Decapeptyl; Ferring GmbH) to routine oocyte triggering (two ampoules of Ovitrelle®, 250 μg/0.5 ml, Merck, Serono, Inc) is defined as dual triggering.
No Intervention: Group B (Routine oocyte triggering approach); Two ampoules of Ovitrelle® (Ovitrelle®, 250 μg/0.5 ml, Merck, Serono, Inc) will be injected subcutaneously for final oocyte triggering.

Outcome Measures

Primary Outcome Measures :

1. Total number of retrieved oocytes [ Time Frame: Day of oocyte pick-up (32-34 hours after hCG administration) ]
   In one hour after ovum pick-up, outcome measurement will be possible.
2. Total number of mature or metaphase II (MII) oocytes [ Time Frame: Day of oocyte pick-up ( 32-34 hours after hCG administration ) ]
   In one hour after ovum pick-up, counting the total number of MII oocytes will be possible.
3. Oocyte recovery ratio [ Time Frame: 32-34 hours after oocyte triggering ]
   Ratio of the total number of follicles above 18 mm to the total number of retrieved oocytes

Secondary Outcome Measures :

1. Fertilization rate [ Time Frame: Day 1 post oocyte retrieval ]
   The number of 2 pronucleus (2pn) oocytes per number of injected and/or inseminated MII oocytes
2. Quality of obtained embryos: grade [ Time Frame: 3 days after in vitro fertilization/ intracytoplasmic sperm injection (IVF/ICSI) procedure ]
   The quality of embryos was graded from 1 to 3 under inverted microscope 3 days after IVF/ICSI procedure. Embryos with even-sized blastomers and/or ≤10% fragments were classified as Grade 1 (Excellent or good quality). Grade 2 embryos (moderate or fair quality) had blastomeres with slightly-moderate size differences and/or 10- 20% fragments. Grade 3 embryos (poor quality) had markedly different-sized blastomers and/or >20% fragments.

Eligibility Criteria

• Ages Eligible for Study: 20 Years to 35 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

Patients with poor ovarian response (POR) diagnosis according to the POSEIDON stratification system (as POSEIDON group 1) with following criteria :

• Women' age under 35 years;
• Previous unexpected poor or suboptimal ovarian response after using conventional protocols (subgroup 1a: < 4 oocytes ) and (subgroup 1b: 4-9 oocytes retrieved)
• Adequate ovarian reserve (antral follicle count ≥5 on menstrual cycle day 2-3; and basal serum AMH ≥ 1.2 ng/ml)

Exclusion Criteria:

• Ovarian failure including basal FSH above 20 IU/l or no antral follicle by ultrasound examination;
• Endometriosis grade 3 or higher;
• Severe male infertility (surgical sperm extraction: TESE, PESA)
• Body mass index >30 kg/ m2
• History of uterine surgery as well as sub-mucosal and intramural fibroids greater than 5 cm or uterine polyps
• Treatment cycles with pre-implantation genetic diagnosis, blastocyst and donation embryo transfer indications
• Cigarette and drug addiction

Contacts and Locations

Contacts

Contact: Parvaneh Afsharian, PhD; +9821- 22339951; pafshar@royaninstitute.org

Locations

Iran, Islamic Republic of

Royan Institute; Recruiting

Tehran, Iran, Islamic Republic of, 16635148

Contact: Maryam Hafezi, M.D. maryamhafezi90@yahoo.com

Contact: Arezoo Arabipoor, M.Sc. arezoo.arabipoor@gmail.com

Sponsors and Collaborators

Royan Institute

Investigators

• Principal Investigator: Maryam Hafezi, M.D.; Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

More Information

• Responsible Party: Royan Institute
• ClinicalTrials.gov Identifier: NCT04549649
• Other Study ID Numbers: Research ID (96000024)
• First Posted: September 16, 2020
• Last Update Posted: December 16, 2020
• Last Verified: December 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: The principle investigator of study can share IPD after finishing the study and publishing the results.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: After finishing the study and publishing the results.
• Access Criteria: Contact the principal investigator by Email.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Royan Institute:

Poor ovarian response; Dual trigger; GnRH antagonist protocol