Clinical trial NCT05847283: DPOS Versus GnRH Antagonist Protocol for Oocyte Accumulation in Low Ovarian Reserve Patients: An RCT
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Diminished Ovarian Reserve
Keywords: Progestin priming ovarian stimulation
Oocyte accumulation
Diminished ovarian reserve
GnRH antagonist
Oocyte vitrification
Dydrogesterone
Lead sponsor: Tam Anh TP. Ho Chi Minh General Hospital
Sponsor class: OTHER
Collaborators: name: Abbott
First posted: 2023-05-06
Enrollment: 730
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 37
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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

Eligibility criteria: 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.
* Patients with a history of thyroid cancer who are on hormone replacement therapy or those diagnosed with thyroid diseases at the time of eligibility assessment

Primary outcomes:
measure: Ongoing pregnancy rate after the first embryo transfer
timeFrame: 11 - 12 weeks of gestation
Secondary outcomes:
measure: Serum LH level
timeFrame: On day 1, day 5, day 8 of FSH administration, on the trigger day and 12 hours after the trigger injection
measure: Serum Estradiol level
timeFrame: On day 1, day 5, day 8 of FSH administration, on the trigger day and 12 hours after the trigger injection
measure: Serum Progesterone level
timeFrame: On day 1, day 5, day 8 of FSH administration, on the trigger day and 12 hours after the trigger injection
measure: Premature LH surge
timeFrame: on the day of trigger, an average of 2 weeks after FSH administration
measure: Duration of ovarian stimulation
timeFrame: From the day 1 of FSH administration to the day of trigger, an average of 2 weeks after FSH administration
measure: Total dose of FSH
timeFrame: From the day 1 of FSH administration to the day of trigger, an average of 2 weeks after FSH administration
measure: Number of Cumulus-oocyte complex
timeFrame: On the oocyte retrieval day, an average of 2 weeks after FSH administration
measure: Number of MII oocyte
timeFrame: On the oocyte retrieval day, an average of 2 weeks after FSH administration
measure: Number of survival oocyte
timeFrame: On the oocyte retrieval day of the ovarian stimulation cycle for ICSI, an average of 2 weeks after FSH administration
measure: Fertilization rate per oocyte inseminated/injected
timeFrame: On the oocyte retrieval day of the ovarian stimulation cycle for ICSI, an average of 2 weeks after FSH administration
measure: Embryo-cleavage rate
timeFrame: Day 3 after ICSI day
measure: Blastocyst rate
timeFrame: Day 5 and Day 6 after ICSI day
measure: Number of survival blastocyst
timeFrame: Day 5 and Day 6 after ICSI day
measure: Top-quality blastocyst rate
timeFrame: Day 5 and Day 6 after ICSI day
measure: Positive pregnancy test
timeFrame: 11 days after the first transfer
measure: Implantation rate
timeFrame: Within 12 weeks of gestation
measure: Biochemical pregnancy
timeFrame: Within 12 weeks of gestation
measure: Miscarriage
timeFrame: Within 12 weeks of gestation
measure: Multiple pregnancy rate
timeFrame: Within 12 weeks of gestation
measure: Ectopic pregnancy rate
timeFrame: Within 12 weeks of gestation
measure: Adverse events
timeFrame: Through study completion of each individual patient, an average of 6 months
measure: Drop-out
timeFrame: Through study completion, approximately within 2 years
measure: Quality of life score
timeFrame: 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
Other outcomes:
Locations:
city: Ho Chi Minh City
country: Vietnam
facility: Ivfta Hcm
state: Ho Chi Minh
city: Hanoi
country: Vietnam
facility: IVFTA
Study officials:
affiliation: Tam Anh TP. Ho Chi Minh General Hospital
name: Nhu H Giang, MD., MCE
role: PRINCIPAL_INVESTIGATOR
References: