DPOS Versus GnRH Antagonist Protocol for Oocyte Accumulation in Low Ovarian Reserve Patients: An RCT

Diminished Ovarian Reserve Clinical Trial

— DPOS  

Official title:

Dydrogesterone Primed Ovarian Stimulation Versus Fixed Gonadotropin Releasing Hormone Antagonist Protocol for Oocyte Accumulation in Low Ovarian Reserve Patients: A Randomized Controlled Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05847283
• Other study ID #: DYDR-C22-0313
• Status: Recruiting
• Phase: N/A
• Start date: June 22, 2023
• Est. completion date: October 31, 2025

Study information

• Verified date: June 2024
• Source: Tam Anh TP. Ho Chi Minh General Hospital
• Contact: Nhu H Giang, MD., MCE
• Phone: +84 793 231 721
• Email: nhugh[@]tahospital.vn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

One of the barriers in patients with diminished ovarian reserve (DOR) is the significantly reduced number of oocytes resulting in fewer oocytes collected and embryos formed. Many ovarian stimulation strategies have been proposed to improve oocyte or embryo quantity which is oocyte accumulation could be a potential option with a comparable success rate and reasonable cost.

Progestin-primed ovarian stimulation (PPOS) protocol could be suggested as an alternative method of premature Luteinizing hormone (LH) prevention in IVF. It favors segment Assisted Reproductive Technology (ART) cycles such as frozen embryo transfer (FET), oocyte donor, fertility preservation, and oocyte accumulation set. The protocol is more patient-friendly and affordable than the GnRH antagonist regimen regarding LH suppression during ovarian stimulation.

Many PPOS protocols have been proposed in which the three most common agents include Dydrogesterone (DYG), Micronised Progesterone (MIP), and Medroxyprogesterone acetate (MPA). Indeed, DYG seems to have some advantages, including oral administration and safety which has been used in the treatment of threatened abortion. Initial evidence of PPOS protocol suggests that oocyte quantity and quality are comparable with other ovarian stimulation regimens. However, data related to the PPOS protocol has not been well documented, including Dydrogesteron-primed ovarian stimulation (DPOS).

There has not been an RCT with a large sample size and well-designed to provide more substantial evidence. A randomized trial to compare the effectiveness of PPOS and GnRH antagonist protocol in IVF is urgently needed.

Description:

Screening for eligibility and randomization

• This trial will be conducted at Tam Anh TP. Ho Chi Minh General hospital, Ho Chi Minh City, Vietnam and Tam Anh General hospital, Ha Noi, Vietnam

• Women who are potentially eligible will be provided information about the trial when IVF treatment is indicated

• Patients will be provided information related to the study together with the informed consent documents. Signed informed consent forms will be obtained by the investigators from all women before the enrolment.

• Women will be randomized (1:1) to either DPOS or GnRH antagonist protocol

Ovarian stimulation

• The patients will be stimulated with the same protocol in all OS cycles after randomization.

• For DPOS arm (Group I): Patients will be co-administered with oral DYG (Duphaston) 30mg/d and Human Menopausal Gonadotrophin (hMG) 225 IU/day (IU/d) via intramuscular injection from menstrual cycle day 2 - 4 (CD2 - CD4) to the day of final oocyte maturation.

• For GnRH antagonist arm (Group II): In the fixed GnRH antagonist protocol, hMG 225 IU will be administered daily from menstrual cycle day 2 - 4 (CD2 - CD4). Daily administration of GnRH antagonist (Ganirelix 0.25 mg) will be initiated on the 5th day of stimulation. Treatment with hMG and GnRH antagonist will be continued daily until the day of final oocyte maturation triggering.

Oocytes retrieval and cryopreservation

• After 36 hours of final maturation injection, all follicles greater than 12mm in diameter will be aspirated.

• Oocyte cryopreservation will be applied to collect at least 7 ± 1 oocytes

• Matured oocytes will be frozen by vitrification (CRYOTEC® Method)

Oocyte thawing and ICSI

• For the last ovarian stimulation cycle, based on the aim to collect at least 7 ± 1 oocytes, the clinician will determine the last ovarian stimulation cycle on the day of final oocyte maturation.

• The frozen oocytes of the previous OS cycle will be thawed; all fresh and frozen oocytes will be fertilized by ICSI.

• The thawing process will follow the CRYOTEC® Method

• ICSI will be used for the fertilization of mature oocytes.

Embryo cryopreservation

• Both the fresh and frozen fertilized oocytes continue to culture in the CXCM medium (Irvine Scientific., USA) to blastocyst.

• Freeze-all strategy is applied in both arms, then the frozen embryo will be transferred in the next cycle.

Endometrium preparation and embryo transfer

• Endometrial preparation with hormonal replacement therapy will be performed. In the following cycle, the endometrium will be prepared using oral estradiol valerate (Valiera®; Laboratories Recalcine) 6 mg/day starting from the second or third day of the menstrual cycle. The endometrial thickness will be monitored from day six onwards, and vaginal progesterone (Cyclogest®; Actavis) 800 mg/day plus dydrogesterone (Duphaston 10mg) at the dose of 10mg twice daily will be started when endometrial thickness reaches 8 mm or more. Elective single blastocyst transfer will be performed.

• Embryos will be thawed on the day of embryo transfer, five or six days after the start of progesterone depending on the day-5 or day-6 embryo, respectively. Embryos will be transferred into the uterine cavity under ultrasound guidance.

Pregnancy test and ultrasound to confirm fetal viability

• A pregnancy test will be performed by measuring the blood beta-hCG level 10 - 11 days after embryo transfer. If the pregnancy test is positive (≥25mIU/mL), the patient is indicated to use exogenous estrogen and progesterone until at least 12 weeks of gestation.

• A pregnancy ultrasound will be performed three weeks after the positive pregnancy test equal to 7 weeks of gestational age.

• The primary endpoint is ongoing pregnancy (11 - 12 weeks of gestation) after the first embryo transfer

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 730
• Est. completion date: October 31, 2025
• Est. primary completion date: October 31, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 37 Years

Eligibility

Inclusion Criteria:

• Woman aged between 18 and 37 years

• AFC = 5 and/or AMH = 1.2 ng/ml

• Agree to perform freeze-all strategy and single frozen blastocyst embryo transfer

Exclusion Criteria:

• Oocyte recipient

• Indication of preimplantation genetic testing

• Known allergic reactions to medications in the Study (progesterone products, GnRH antagonist….)

• Basal FSH above 15mIU/mL.

• Have contraindications of ART treatment (e.g. critical or acute diseases)

• Retrieved sperm

• Repeated Implantation failure ( = 3 failed embryo transfers with good-quality embryos)

• Inability to comply with the study procedures.

Related Conditions & MeSH terms

• Diminished Ovarian Reserve

Intervention

Procedure:
• Dydrogesterone priming ovarian stiumulation protocol
Patients will be co-administered with oral DYG (Duphaston) 30mg/d and Human Menopausal Gonadotrophin (hMG) 225 IU/day (IU/d) via intramuscular injection from menstrual cycle day 2 - 4 (CD2 - CD4) to the day of final oocyte maturation.
• GnRH antagonist protocol
In the fixed GnRH antagonist protocol, hMG 225 IU will be administered daily from menstrual cycle day 2 - 4 (CD2 - CD4) and s.c. administration of GnRH antagonist (Ganirelix 0.25 mg) will be initiated daily on the 5th day of stimulation. Treatment with hMG and GnRH antagonist will be continued until the day of final oocyte maturation triggering.

Locations

Country	Name	City	State
Vietnam	IVFTA	Hanoi
Vietnam	Ivfta Hcm	Ho Chi Minh City	Ho Chi Minh

Sponsors (2)

Lead Sponsor	Collaborator
Tam Anh TP. Ho Chi Minh General Hospital	Abbott

Country where clinical trial is conducted

Vietnam, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Ongoing pregnancy rate after the first embryo transfer	Ongoing pregnancy is defined as pregnancy with a detectable heart rate at 11 - 12 weeks of gestation after the completion of the first transfer.	11 - 12 weeks of gestation
Secondary	Serum LH level	LH levels are measured on day 1, day 5, day 8 of FSH administration, on the trigger day and 12 hours after the trigger injection	On day 1, day 5, day 8 of FSH administration, on the trigger day and 12 hours after the trigger injection
Secondary	Serum Estradiol level	Estradiol levels are measured on day 1, day 5, day 8 of FSH administration, on the trigger day and 12 hours after the trigger injection	On day 1, day 5, day 8 of FSH administration, on the trigger day and 12 hours after the trigger injection
Secondary	Serum Progesterone level	Progesterone levels are measured on day 1, day 5, day 8 of FSH administration, on the trigger day and 12 hours after the trigger injection	On day 1, day 5, day 8 of FSH administration, on the trigger day and 12 hours after the trigger injection
Secondary	Premature LH surge	Premature LH surge (PLS) is increased serum LH more than twice the baseline or more than 15 mIU/ml. The rate of Premature LH surge is defined as number of PLS appearances per number of ovarian stimulation cycles	on the day of trigger, an average of 2 weeks after FSH administration
Secondary	Duration of ovarian stimulation	Number of ovarian stimulation days	From the day 1 of FSH administration to the day of trigger, an average of 2 weeks after FSH administration
Secondary	Total dose of FSH	A number of international units of FSH are administrated during an ovarian stimulation cycle	From the day 1 of FSH administration to the day of trigger, an average of 2 weeks after FSH administration
Secondary	Number of Cumulus-oocyte complex	Number of Cumulus-oocyte complexes after oocyte retrieval	On the oocyte retrieval day, an average of 2 weeks after FSH administration
Secondary	Number of MII oocyte	Number of MII oocytes after denuding	On the oocyte retrieval day, an average of 2 weeks after FSH administration
Secondary	Number of survival oocyte	Number of survival oocytes after thawing	On the oocyte retrieval day of the ovarian stimulation cycle for ICSI, an average of 2 weeks after FSH administration
Secondary	Fertilization rate per oocyte inseminated/injected	Fertilization is defined as the appearance of two PN at 17±1 hour per inseminated/injected	On the oocyte retrieval day of the ovarian stimulation cycle for ICSI, an average of 2 weeks after FSH administration
Secondary	Embryo-cleavage rate	Number of embryos on Day 3 after ICSI day	Day 3 after ICSI day
Secondary	Blastocyst rate	Numbers of embryos on Day 5 and Day 6 after ICSI	Day 5 and Day 6 after ICSI day
Secondary	Number of survival blastocyst	Number of survival embryos on Day 5 and Day 6 after thawing	Day 5 and Day 6 after ICSI day
Secondary	Top-quality blastocyst rate	Numbers of embryos on Day 5 and Day 6 with good quality after ICSI	Day 5 and Day 6 after ICSI day
Secondary	Positive pregnancy test	A positive pregnancy test is defined as a serum hCG level greater than 25 mIU/mL 11 days after the first transfer	11 days after the first transfer
Secondary	Implantation rate	Implantation rate is defined as the number of gestational sacs per number of embryos transferred 3 weeks after the first transfer	Within 12 weeks of gestation
Secondary	Biochemical pregnancy	Biochemical pregnancy is defined as a pregnancy diagnosed only by the detection of beta hCG in serum or urine	Within 12 weeks of gestation
Secondary	Miscarriage	Complete loss of clinical pregnancy at 12 weeks of gestation	Within 12 weeks of gestation
Secondary	Multiple pregnancy rate	Multiple pregnancy rate is explained as two or more gestational sacs or positive heartbeats by transvaginal sonography 5 weeks after embryo placement	Within 12 weeks of gestation
Secondary	Ectopic pregnancy rate	Ectopic pregnancy confirmed by sonography or laparoscopy at 12 weeks of gestation	Within 12 weeks of gestation
Secondary	Adverse events	Adverse events regarding medications according to local information products	Through study completion of each individual patient, an average of 6 months
Secondary	Drop-out	Drop-out is defined as any patient discontinuing the Study or the investigator withdrawing them from the Study for any reason.	Through study completion, approximately within 2 years
Secondary	Quality of life score	Quality of life is assessed by Vietnamese WHO-BRIFE questionnaire	On day 1 of FSH administration of the first ovarian stimulation cycle for oocyte vitrification and on the trigger day of the ovarian stimulation cycle for ICSI