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

Study Overview
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Brief Summary
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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
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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

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

Conditions
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Diminished Ovarian Reserve

Intervention / Treatment
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* Procedure: Dydrogesterone priming ovarian stiumulation protocol
* Procedure: GnRH antagonist protocol


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 37 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: DPOS protocol<br>Women will receive oral Dydrogesterone 10mg (Duphaston 10mg) t.i.d daily from the first day of ovarian stimulation till the day of final oocyte maturation. | Procedure: Dydrogesterone priming ovarian stiumulation protocol<br>* 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.<br>* Other names: DPOS protocol;|
| Placebo Comparator: GnRH antagonist protocol<br>Women will receive GnRH antagonist (Ganirelix 0.25mg) once subcutaneously daily from day 5 of ovarian stimulation till the day of final oocyte maturation | Procedure: GnRH antagonist protocol<br>* 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.<br>* Other names: GnRHanta protocol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Number of MII oocyte | Number of MII oocytes after denuding | On the oocyte retrieval day, an average of 2 weeks after FSH administration | 
| 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 | 
| 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 | 
| Embryo-cleavage rate | Number of embryos on Day 3 after ICSI day | Day 3 after ICSI day | 
| Blastocyst rate | Numbers of embryos on Day 5 and Day 6 after ICSI | Day 5 and Day 6 after ICSI day | 
| Number of survival blastocyst | Number of survival embryos on Day 5 and Day 6 after thawing | Day 5 and Day 6 after ICSI day | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Miscarriage | Complete loss of clinical pregnancy at 12 weeks of gestation | Within 12 weeks of gestation | 
| 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 | 
| Ectopic pregnancy rate | Ectopic pregnancy confirmed by sonography or laparoscopy at 12 weeks of gestation | Within 12 weeks of gestation | 
| Adverse events | Adverse events regarding medications according to local information products | Through study completion of each individual patient, an average of 6 months | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Progestin priming ovarian stimulation, Oocyte accumulation, Diminished ovarian reserve, GnRH antagonist, Oocyte vitrification, Dydrogesterone