Clinical trial NCT06378268: PPOS vs GnRH Antagonist in Ovarian Stimulation (ProGanOS Study)
Official title: Effectiveness of Progestin-Primed Ovarian Stimulation Versus GnRH Antagonist Protocol for Ovarian Stimulation in IVF: a Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Progestins Primed Ovarian Stimulation
Keywords: Progestins Primed Ovarian Stimulation
GnRH antagonist
ongoing pregnancy
Lead sponsor: Mỹ Đức Hospital
Sponsor class: OTHER
First posted: 2024-04-22
Enrollment: 626
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This non-inferiority randomized controlled trial will be conducted at My Duc Hospital, Ho Chi Minh City, Vietnam.

This study compares the effectiveness of Progestin-Primed Ovarian stimulation versus GnRH protocol for ovarian stimulation in IVF treatment. Participants will be randomly assigned in a 1:1 ratio to receive Progestins or GnRH antagonists.

Detailed description: Study Procedures

Participants will be randomized into two arms:

* PPOS group: Recombinant FSH 150-300 IU/day will start from day 2 to day 4 of menstruation. The initial FSH dose will be chosen based on age, anti-Müllerian hormone (AMH) level, antral follicle count (AFC), and body mass index (BMI). The FSH dosage will be fixed during ovarian stimulation. Dydrogesterone (Duphaston, Abbott, USA) 20mg/day will start on the day of gonadotropin injection to the oocyte maturation trigger night.
* GnRH antagonist group: Recombinant FSH 150-300 IU/day will be given from day 2 to day 4 of menstruation. The initial FSH dose will be chosen based on age, anti-Müllerian hormone (AMH) level, antral follicle count (AFC), and body mass index (BMI). The FSH dosage will be fixed during ovarian stimulation. Cetrorelix (Cetrotide, Merck, Germany) 0.25mg/day will be given from day 5 of stimulation by the oocyte maturation trigger day.

Follicular monitoring will start on the fifth or sixth day of ovarian stimulation and was performed every 3-5 days thereafter using transvaginal ultrasound to record the number of developing follicles. Measuring LH, estradiol, and progesterone serum levels will be performed on the fifth or sixth day of ovarian stimulation and oocyte maturation day (before the trigger injection). The FSH dosage will be fixed during ovarian stimulation. When more than two dominant follicles reach a diameter of at least 17mm, \>= 50% diameter of remaining follicles cohort \>=12 mm, the final stage of oocyte maturation will trigger using human chorionic gonadotropin (hCG; IVF-C 10.000 IU, LG Chem, Ltd., Korea or Ovitrelle Pen 250µg, Merck Serono S.p.A., Italy). In individuals who are at high risk for OHSS, GnRH agonist trigger 0.2mg (Diphereline 0.2mg, Ipsen Pharma, France) will given subcutaneously.

Transvaginal ultrasound-guided oocyte retrieval will be performed 34-36 hours after trigger, with the retrieval of all follicles exceeding 10mm in diameter. Oocyte fertilization will be carried out in vitro using ICSI. On the third day after fertilization, embryos will be evaluated for the degree of embryonic fragmentation, regularity, and number of blastomeres in accordance with the Istanbul consensus (Alpha Scientists in Reproductive Medicine and ESHRE Special Interest Group of Embryology, 2011). Day 3 embryos will be cryopreserved or cultured until the blastocyst stage based on physician recommendation or patient references; viable blastocysts will then be cryopreserved on day 5 or day 6.

Endometrial preparation for frozen embryo transfer (FET) will be given using an exogenous steroid regimen from day 2 to day 4 of the menstrual cycle. Oral estradiol valerate (Progynova, Bayer Schering Pharma, Germany) 8mg/day will be given for 10-12 days. When endometrial thickness reaches ≥ 7mm, along with a triple-line pattern, micronized progesterone 800mg will be administered. FET will be performed three to five days after progesterone administration. There will be no more than 2 embryo(s) transfers each FET cycle. After FET, estradiol and progesterone supplementation will be continued for all participants until the day of taking the pregnancy test. Participants with a positive pregnancy test continued to receive oral estradiol valerate 8mg/day and micronized progesterone 800mg/day until the fetal heart appeared, and then only micronized progesterone 800mg will be used until 12 weeks of gestation.

All participants will be followed up per local protocol until outcomes are achieved.

Eligibility criteria: Inclusion Criteria:

* Woman aged 18-40
* BMI ≤ 25kg/m2
* AMH \> 1.2ng/mL or AFC \>5
* Having indication for IVF treatment
* Agree to have frozen embryo(s) transfer
* Not participating in any other clinical trials
* Provision of written informed consent to participate

Exclusion Criteria:

* Undergoing IVF cycle with other protocols: Down-regulation, mild stimulation, Random start
* Oocyte donation cycles
* Undergoing vitrified oocyte accumulation
* Oocyte cryopreservation
* Cycle with PGT (Preimplatation genetic testing)
* Women with PCOS
* Women allergy to dydrogesterone, rFSH, GnRH antagonist

Primary outcomes:
measure: Ongoing pregnancy
timeFrame: At 10 weeks after embryo(s) placement
Secondary outcomes:
measure: The incidence of premature LH surge
timeFrame: On the day having indication of oocyte maturation
measure: The incidence of premature progesterone elevation
timeFrame: On the day having indication of oocyte maturation
measure: Number of oocytes retrieved
timeFrame: On the oocyte(s) retrieval day
measure: Number of mature oocytes
timeFrame: On the oocyte(s) retrieval day
measure: Number of day 3 embryos
timeFrame: At 62-66 hours after ICSI
measure: Number of day 5 embryos
timeFrame: At 112-116 hours after ICSI
measure: Number of good quality day 3 embryos
timeFrame: At 62-66 hours after ICSI
measure: Number of good quality day 5 embryos
timeFrame: At 112-116 hours after ICSI
measure: Number of frozen embryos
timeFrame: at 112-116 hours after ICSI
measure: Incidence of Ovarian hyperstimulation syndrome
timeFrame: At 2 weeks after trigger
measure: Positive ß-hCG test
timeFrame: At 2 weeks after embryo(s) placement
measure: Clinical pregnancy
timeFrame: at 6 weeks or more after the onset of last menstrual period
measure: Ectopic pregnancy
timeFrame: at 6 weeks after the onset of last menstrual period
measure: Early miscarriage <12 weeks
timeFrame: At 12 weeks of gestation
measure: Late miscariage 12-< 22 weeks
timeFrame: between 12 to 22 completed weeks of gestational age
measure: Live birth rate
timeFrame: At 22 weeks of gestation
measure: Gestational age at birth
timeFrame: At birth
measure: Mode of delivery
timeFrame: At birth
measure: Birth weight
timeFrame: At birth
measure: Very low birth weight
timeFrame: At birth
measure: Low birth weight
timeFrame: At birth
measure: High birth weight
timeFrame: At birth
measure: Very high birth weight
timeFrame: At birth
measure: Preterm birth
timeFrame: At birth
measure: Gestational diabetes mellitus
timeFrame: At 24 to 28 weeks of gestation
measure: Hypertensive disorders of pregnancy
timeFrame: At 20 weeks of gestation or beyond
measure: Maternal mortality
timeFrame: From randomization to within 42 days of termination of pregnancy
measure: Major congenital abnormalities
timeFrame: From randomization to delivery
measure: NICU admission
timeFrame: at birth
measure: Reason for NICU admission
timeFrame: at birth
measure: Neonatal mortality
timeFrame: within 28 days of birth
Other outcomes:
Locations:
city: Ho Chi Minh City
country: Vietnam
facility: My Duc Hospital
Study officials:
affiliation: University of Medicine and Pharmacy at Ho Chi Minh City
name: Lan N Vuong, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Messinis IE. Ovarian feedback, mechanism of action and possible clinical implications. Hum Reprod Update. 2006 Sep-Oct;12(5):557-71. doi: 10.1093/humupd/dml020. Epub 2006 May 3.
citation: Papanikolaou EG, Kolibianakis EM, Pozzobon C, Tank P, Tournaye H, Bourgain C, Van Steirteghem A, Devroey P. Progesterone rise on the day of human chorionic gonadotropin administration impairs pregnancy outcome in day 3 single-embryo transfer, while has no effect on day 5 single blastocyst transfer. Fertil Steril. 2009 Mar;91(3):949-52. doi: 10.1016/j.fertnstert.2006.12.064. Epub 2007 Jun 6.
citation: Van Vaerenbergh I, Fatemi HM, Blockeel C, Van Lommel L, In't Veld P, Schuit F, Kolibianakis EM, Devroey P, Bourgain C. Progesterone rise on HCG day in GnRH antagonist/rFSH stimulated cycles affects endometrial gene expression. Reprod Biomed Online. 2011 Mar;22(3):263-71. doi: 10.1016/j.rbmo.2010.11.002. Epub 2010 Nov 13.
citation: Droesch K, Muasher SJ, Brzyski RG, Jones GS, Simonetti S, Liu HC, Rosenwaks Z. Value of suppression with a gonadotropin-releasing hormone agonist prior to gonadotropin stimulation for in vitro fertilization. Fertil Steril. 1989 Feb;51(2):292-7. doi: 10.1016/s0015-0282(16)60493-4.
citation: van Loenen AC, Huirne JA, Schats R, Hompes PG, Lambalk CB. GnRH agonists, antagonists, and assisted conception. Semin Reprod Med. 2002 Nov;20(4):349-64. doi: 10.1055/s-2002-36713.
citation: Al-Inany HG, Youssef MA, Aboulghar M, Broekmans F, Sterrenburg M, Smit J, Abou-Setta AM. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev. 2011 May 11;(5):CD001750. doi: 10.1002/14651858.CD001750.pub3.
citation: Toftager M, Bogstad J, Bryndorf T, Lossl K, Roskaer J, Holland T, Praetorius L, Zedeler A, Nilas L, Pinborg A. Risk of severe ovarian hyperstimulation syndrome in GnRH antagonist versus GnRH agonist protocol: RCT including 1050 first IVF/ICSI cycles. Hum Reprod. 2016 Jun;31(6):1253-64. doi: 10.1093/humrep/dew051. Epub 2016 Apr 8.
citation: Griesinger G, Schultz L, Bauer T, Broessner A, Frambach T, Kissler S. Ovarian hyperstimulation syndrome prevention by gonadotropin-releasing hormone agonist triggering of final oocyte maturation in a gonadotropin-releasing hormone antagonist protocol in combination with a "freeze-all" strategy: a prospective multicentric study. Fertil Steril. 2011 May;95(6):2029-33, 2033.e1. doi: 10.1016/j.fertnstert.2011.01.163. Epub 2011 Mar 2.
citation: Kuang Y, Chen Q, Fu Y, Wang Y, Hong Q, Lyu Q, Ai A, Shoham Z. Medroxyprogesterone acetate is an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization. Fertil Steril. 2015 Jul;104(1):62-70.e3. doi: 10.1016/j.fertnstert.2015.03.022. Epub 2015 May 5.
citation: Wang Y, Chen Q, Wang N, Chen H, Lyu Q, Kuang Y. Controlled Ovarian Stimulation Using Medroxyprogesterone Acetate and hMG in Patients With Polycystic Ovary Syndrome Treated for IVF: A Double-Blind Randomized Crossover Clinical Trial. Medicine (Baltimore). 2016 Mar;95(9):e2939. doi: 10.1097/MD.0000000000002939.
citation: Zhu X, Ye H, Fu Y. The Utrogestan and hMG protocol in patients with polycystic ovarian syndrome undergoing controlled ovarian hyperstimulation during IVF/ICSI treatments. Medicine (Baltimore). 2016 Jul;95(28):e4193. doi: 10.1097/MD.0000000000004193.
citation: Massin N. New stimulation regimens: endogenous and exogenous progesterone use to block the LH surge during ovarian stimulation for IVF. Hum Reprod Update. 2017 Mar 1;23(2):211-220. doi: 10.1093/humupd/dmw047.
citation: Vuong LN, Dang VQ, Ho TM, Huynh BG, Ha DT, Pham TD, Nguyen LK, Norman RJ, Mol BW. IVF Transfer of Fresh or Frozen Embryos in Women without Polycystic Ovaries. N Engl J Med. 2018 Jan 11;378(2):137-147. doi: 10.1056/NEJMoa1703768.
citation: Shrestha D, La X, Feng HL. Comparison of different stimulation protocols used in in vitro fertilization: a review. Ann Transl Med. 2015 Jun;3(10):137. doi: 10.3978/j.issn.2305-5839.2015.04.09.
citation: Ferin M, Rosenblatt H, Carmel PW, Antunes JL, Vande Wiele RL. Estrogen-induced gonadotropin surges in female rhesus monkeys after pituitary stalk section. Endocrinology. 1979 Jan;104(1):50-2. doi: 10.1210/endo-104-1-50.
citation: Leroy I, d'Acremont M, Brailly-Tabard S, Frydman R, de Mouzon J, Bouchard P. A single injection of a gonadotropin-releasing hormone (GnRH) antagonist (Cetrorelix) postpones the luteinizing hormone (LH) surge: further evidence for the role of GnRH during the LH surge. Fertil Steril. 1994 Sep;62(3):461-7. doi: 10.1016/s0015-0282(16)56932-5.