GnRh Antagonist Protocol With Delayed Start Stimulation in Patients With Poor Ovarian Response

Evaluation of a Novel " Delayed Start" Protocol With Gonadotropin-releasing Hormone Antagonist in Poor Responders: A Randomized Clinical Trial Phase 3

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 Overview

• Status: Completed
• Conditions: Infertility, Female
• Intervention / Treatment: Procedure: delayed start; Procedure: Conventional

Detailed Description

One of the principal steps to obtain the favorable success is still related to the number of retrieved oocytes after hormonal stimulation by gonadotropins in combination with GnRH analogues. In the patients with "poor ovarian response" diagnosis, the limited number of obtained oocytes remains the main obstacle in optimizing the live birth rates. The objective of present study is to evaluate a new procedure to increase a cohort of the growing antral follicles and consequently the number of retrieved oocytes after hormonal stimulation by gonadotropins in combination with GnRH antagonist. In present study, eligible patients with diagnosis poor ovarian responder based on the Bologna criteria are included. Ovarian stimulation procedure will be performed by antagonist protocol. All the patients will be received two tablets daily of Estradiol valerate (Estraval®, 2 mg, Aburaihan Co., Tehran, Iran) starting a week after LH surge until menses. The hormonal evaluation (serum LH and FSH) and basic vaginal ultrasound will be performed before the starting ovarian stimulation on the 2th or 3th day of the menstrual cycle. On this day, the block randomization method will be designed to randomize allocation of patients into groups with blocks of size 4.

In the Group A: treatment with GnRH antagonists (Cetrotide®, 0.25 mg cetrorelix acetate, Serono, Inc) will be started on the 2th or 3th day of the menstrual cycle and continues until the ninth day. Then, the ovarian stimulation with gonadotropin 300 IU recombinant FSH (Gonal - F®, Serono Laboratories Ltd, Geneva, Switzerland) and 150 IU of hMG (Menopur®; Ferring) will be started from ninth day of menstrual cycle until the day of hCG administration. The monitoring of ovarian stimulation will be done every other day by vaginal ultrasound and whenever at least 1 to 3 follicles larger than 13 mm are observed, the antagonist injection (Cetrotide®, 0.25 mg cetrorelix acetate, Serono, Inc) will be started again to prevent premature LH surge and continues until the prescription of hCG. When at least two follicles greater than 17 to 18 mm is seen, two pre-filled syringes of recombinant human chorionic gonadotropin (rhCG) (Ovitrelle®, 250 μg/0.5 ml, Merck, Serono, Inc) will be administered. The patients will undergo puncture operation 32-34 hours after hCG injection.

In the control group (B), as conventional antagonist procedure, the ovarian stimulation with gonadotropin 300 IU recombinant FSH (Gonal - F®, Serono Laboratories Ltd, Geneva, Switzerland) and 150 IU of hMG ( Menopur®; Ferring ) will be started from on the 2th or 3th day of the menstrual cycle. The monitoring of ovarian stimulation will be done every other day by vaginal ultrasound and whenever at least 1 to 3 follicles larger than 13 mm are observed, the antagonist injection (Cetrotide®, 0.25 mg cetrorelix acetate, Serono, Inc) will be started again to prevent premature LH surge and continues until the prescription of rhCG. 32-34 hours after the rhCG injection, the ovum pick up will be performed and subsequently intracytoplasmic sperm injection (ICSI) /in-vitro fertilization (IVF) will be done for all the patients.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Iran, Islamic Republic of
  • Tehran, Iran, Islamic Republic of
    • Royan Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Poor ovarian response is defined according to the Bologna criteria and existence of at least two of the following criteria:

1. a previous history of POR (retrieved oocytes ≤3) in a conventional stimulation protocol,
2. advanced maternal age (≥40 years) or any other risk factors for POR (e.g. a history of ovarian surgery)
3. abnormal ovarian reserve test (i.e. antral follicle count (AFC) < 5 follicles or anti-Mȕllerian hormone (AMH) < 1.1 ng/ml)

Exclusion Criteria:

1. Premature ovarian failure (basal follicle stimulating hormone (FSH) above 20 IU/l or no antral follicle in ultrasound examination),
2. ِDonor/recipient treatments,
3. Metabolic or endocrine disorders including hyperprolactinoma and hypo/hyperthyroidism, endometriosis,
4. Body mass index > 30 kg/m2,
5. azoospermic male partner.
6. A minimum of 2 or more month's interval from the previous ovarian stimulation is considered to prevent any potential source of error.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: delayed start antagonist; 60 women with poor ovarian responses undergo ovarian stimulation with delayed start antagonist.	Procedure: delayed start; In this protocol, ovarian stimulation will be started from ninth day of menstrual cycle .
EXPERIMENTAL: conventional antagonist; 60 women with diagnose of poor ovarian response will have undergone ovarian stimulation with conventional antagonist protocol.	Procedure: Conventional; In this protocol, ovarian stimulation will be started from the 2th or 3th day of the menstrual cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
number of dominant follicles (≥13 mm)	The number of dominant follicles (≥13 mm) on the day of hCG trigger	24h after rhCG injection
Total number of oocytes	the number of mature oocytes collected after conventional versus delayed-start ovarian stimulation protocol	32-34 hours after rhCG

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total number of retrieved oocytes	Total number of retrieved oocytes 32-34 hours after rhCG injection .	32-34 hours after rhCG injection
Quality of obtained embryos	we score embryo quality according to the following quality criteria: Excellent (Day 3: 6-8 even size blastomeres with ≤10% fragmentation), Good (Day 3: 6-8 even or uneven size blastomeres with 10%-20% fragmentation), Poor (Uneven and few blastomeres with >20% fragmentation)	on the third day after oocyte retrieval

Collaborators and Investigators

• Sponsor: Royan Institute
• Investigators: Study Director: Mahnaz Ashrafi, MD, Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, ACECR, Tehran, Iran; Principal Investigator: Mandana Hemmat, MD, Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, ACECR, Tehran, Iran; Principal Investigator: Arezoo Arabipour, MSc, Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, ACECR, Tehran, Iran

Publications and helpful links

General Publications

• Ashrafi M, Arabipoor A, Yahyaei A, Zolfaghari Z, Ghaffari F. Does the "delayed start" protocol with gonadotropin-releasing hormone antagonist improve the pregnancy outcome in Bologna poor responders? a randomized clinical trial. Reprod Biol Endocrinol. 2018 Dec 28;16(1):124. doi: 10.1186/s12958-018-0442-y.

Study record dates

Study Major Dates

• Study Start: January 1, 2016
• Primary Completion (ACTUAL): April 1, 2018
• Study Completion (ACTUAL): June 1, 2018

Study Registration Dates

• First Submitted: December 19, 2016
• First Submitted That Met QC Criteria: April 26, 2017
• First Posted (ACTUAL): May 1, 2017

Study Record Updates

• Last Update Posted (ACTUAL): February 8, 2023
• Last Update Submitted That Met QC Criteria: February 6, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Poor ovarian response gonadotropins antagonist
• Additional Relevant MeSH Terms: Infertility; Infertility, Female
• Other Study ID Numbers: Royan-Emb-028

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No