Clinical trial NCT03405701: IVM Versus IVF in High Antral Follicle Count Patients
Official title: The Effectiveness and Safety of in Vitro Maturation of Oocytes Versus in Vitro Fertilization in Women With High Antral Follicle Count (AFC): a Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: PCOS
IVF
IVM
Lead sponsor: Mỹ Đức Hospital
Sponsor class: OTHER
First posted: 2018-01-23
Enrollment: 546
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: In vitro maturation (IVM) is postulated to be an alternative to conventional in vitro fertilization (IVF) to avoid ovarian hyperstimulation syndrome. This has particular potential in women with Polycystic Ovarian Syndrome (PCOS), who are at increased risk for the ovarian hyperstimulation syndrome. However, no randomized controlled trials on the comparison of IVM and conventional IVF in women with PCOS have been reported with respect to pregnancy rate and hyper-stimulation. Investigators aim to compare the effectiveness and safety of IVM with controlled ovarian hyperstimulation/IVF in women with high antral follicle count.

Detailed description: Women with PCOS and PCOM or high AFC: ≥24 Antral Follicles in Both Ovaries will be given the information about the study during the first consultation which is at least 2 weeks before having periods. On the second day of periods, women will be screened for eligibility by the treating clinicians. Women who met the inclusion criteria will be invited to participate in the study. Women will be randomized (1:1) to IVM or IVF- GnRH agonist triggering cycle using block randomization by an independent study coordinator via telephone, using a computer-generated random list (block size 2, 4, 6 or 8).

Group 1: IVM Patients with a normal cycle length (\>/=35 days) will receive injected highly purified human menopausal gonadotropin (hp-hMG; Menopur, Ferring) 150 IU/day starting on day two or three of the spontaneous menstrual cycle. Oocyte retrieval will be performed 42 hours after the last hp-hMG injection. Women who do not have a normal cycle length (\>35 days; 4-9 menstrual cycles in a year or amenorrhea) will take an oral contraceptive for 2 weeks, then receive hp-hMG 150 IU/day (hp-hMG; Menopur, Ferring injection for 2 days starting 5 days later.

In all patients, ultrasound will be performed on the second day of gonadotrophin injection and OPU is scheduled for 42 hours after the last gonadotrophin injection. After oocyte pick-up, all oocytes will be placed in pre-maturation medium (CAPA Pre-maturation in Medicult IVM medium, Origio, Denmark) for 24 hours, then transferred to maturation culture (Medicult IVM system with phenol red, Origio, Denmark) for 30 hours.

Group 2: IVF All women in this group will undergo COH using a hp-hMG/GnRH antagonist protocol, with an hp-hMG dose of 150-225 IU/day (Menopur, Ferring), depending on age and body mass index. Follicular development will be monitored using ultrasound scanning, and estradiol and progesterone levels. When at least two leading follicles reach 17 mm in diameter, GnRH agonist (GnRHa) triggering with triptorelin 0.2 mg (Diphereline, Ipsen Beaufour) will be administered, and oocyte retrieval performed 36 hours later.

Laboratory procedures For both groups, insemination will be performed using intra-cytoplasmic sperm injection (3-4 hours after oocyte retrieval or maturation check); only matured oocytes will be inseminated. Fertilization check will be performed under an inverted microscope at 16-18 hours after insemination. Embryo evaluation will be performed at 68 ±1 hours after fertilization using the Istanbul consensus.

Freeze-all and Frozen embryo transfer In both groups, all embryos will be frozen on day 3. Frozen transfer of a maximum of 2 embryos will be performed in a subsequent cycle using HRT for endometrial preparation.

In the following cycle, the endometrium will be prepared using oral estradiol valerate (Valiera®; Laboratories Recalcine) 8 mg/day starting from the second or third day of the menstrual cycle. Endometrial thickness will be monitored from day six onwards, and vaginal progesterone (Cyclogest®; Actavis) 800 mg/day will be started when endometrial thickness reached 8 mm or more. A maximum of 2 embryos will be thawed on the day of embryo transfer, three days after the start of progesterone. Two hours after thawing, surviving embryos will be transferred into the uterus under ultrasound guidance. When women had more than two embryos frozen, the procedure will be repeated in subsequent cycles if they fail the first transfer.

Eligibility criteria: Inclusion Criteria:

* Women with high AFC (≥24 Antral Follicles in Both Ovaries), including PCOS plus PCO or high AFC
* Having indications for ART
* Having ≤ 2 IVM/IVF attempts
* Permanent resident in Vietnam
* Agree to have all embryos frozen on day 3
* Agree to have ≤ 2 embryos transferred in a subsequent frozen transfer
* Not participating in another IVF study at the same time

Exclusion Criteria:

* Oocyte donation cycles
* Pre-implantation genetic diagnosis (PGD) cycles

Primary outcomes:
measure: Live birth after the first embryo transfer of the started treatment cycle
timeFrame: 12 weeks of gestation
Secondary outcomes:
measure: Positive pregnancy test
timeFrame: at 2 weeks after the embryo placement after the completion of the first transfer
measure: Clinical pregnancy
timeFrame: 5 weeks after embryo placement after the completion of the first transfer
measure: Ongoing pregnancy
timeFrame: at 10 weeks or beyond after the embryo placement after the completion of the first transfer
measure: Implantation rate
timeFrame: 3 weeks after embryo transferred after the completion of the first transfer
measure: Number of top quality embryos
timeFrame: 3 days after oocytes pick-up day in IVF or 5 days in IVM
measure: Number of freezable embryos
timeFrame: 3 days after oocytes pick-up day in IVF or 5 days in IVM after the completion of the first transfer
measure: Time from randomisation to ongoing pregnancy
timeFrame: 12 weeks of gestation after the completion of the first transfer
measure: Cumulative ongoing pregnancy at 6 months
timeFrame: at 6 months after randomization
measure: Cumulative ongoing pregnancy at 12 months
timeFrame: at 12 months after randomization
Other outcomes:
measure: Ovarian hyperstimulation syndrome (OHSS)
timeFrame: at 03 days after oocytes pick-up and 14 days after embryo transfer
measure: Ectopic pregnancy
timeFrame: at 12 weeks of gestation after the completion of the first transfer
measure: Ectopic pregnancy
timeFrame: at 6 months after randomisation
measure: Ectopic pregnancy
timeFrame: at 12 months after randomisation
measure: Miscarriage
timeFrame: at 24 weeks of gestation after the completion of the first transfer
measure: Miscarriage
timeFrame: At 6 months after randomisation
measure: Miscarriage
timeFrame: at 12 months after randomisation
measure: Hypertensive disorders of pregnancy
timeFrame: at 20 weeks of gestation or beyond after the completion of the first transfer
measure: Hypertensive disorders of pregnancy
timeFrame: at 20 weeks of gestation or beyond at 6 months after randomisation
measure: Hypertensive disorders of pregnancy
timeFrame: at 20 weeks of gestation or beyond at 12 months after randomisation
measure: Gestational diabetes mellitus
timeFrame: at 24 weeks of gestation after the completion of the first transfer
measure: Gestational diabetes mellitus
timeFrame: at 24 weeks of gestation at 6 months after randomisation
measure: Gestational diabetes mellitus
timeFrame: at 24 weeks of gestation at 12 months after randomisation
measure: Preterm delivery
timeFrame: at 24, 28, 32 weeks and 37 weeks of gestation after the completion of the first transfer
measure: Preterm delivery
timeFrame: at 24, 28, 32 weeks and 37 weeks of gestation at 6 months after randomisation
measure: Preterm delivery
timeFrame: at 24, 28, 32 weeks and 37 weeks of gestation at 12 months after randomisation
measure: Multiple pregnancy
timeFrame: after the completion of the first transfer
measure: Multiple pregnancy
timeFrame: at 6 months after randomisation
measure: Multiple pregnancy
timeFrame: at 12 months after randomisation
measure: Multiple delivery
timeFrame: 22 weeks of gestation or beyond after the completion of the first transfer
measure: Multiple delivery
timeFrame: 22 weeks of gestation or beyond at 6 months after randomisation
measure: Multiple delivery
timeFrame: 22 weeks of gestation or beyond at 12 months after randomisation
measure: Antepartum haemorrhage
timeFrame: After the completion of the first transfer
measure: Antepartum haemorrhage
timeFrame: At 6 months after randomisation
measure: Antepartum haemorrhage
timeFrame: At 12 months after randomisation
measure: Spontaneous preterm birth
timeFrame: at 24, 28, 32 weeks and 37 weeks of gestation after the completion of the first transfer
measure: Spontaneous preterm birth
timeFrame: at 24, 28, 32 weeks and 37 weeks of gestation at 6 months after randomisation
measure: Spontaneous preterm birth
timeFrame: at 24, 28, 32 weeks and 37 weeks of gestation at 12 months after randomisation
measure: Iatrogenic preterm birth
timeFrame: at 24, 28, 32 weeks and 37 weeks of gestation after the completion of the first transfer
measure: Iatrogenic preterm birth
timeFrame: at 24, 28, 32 weeks and 37 weeks of gestation at 6 months after randomisation
measure: Iatrogenic preterm birth
timeFrame: at 24, 28, 32 weeks and 37 weeks of gestation at 12 months after randomisation
measure: Birth weight
timeFrame: at the time of delivery
measure: Large for gestational age
timeFrame: at the time of delivery after the completion of the first transfer
measure: Large for gestational age
timeFrame: at the time of delivery at 6 months after randomisation
measure: Large for gestational age
timeFrame: at the time of delivery at 12 months after randomisation
measure: Small for gestational age
timeFrame: at the time of delivery after the completion of the first transfer
measure: Small for gestational age
timeFrame: at the time of delivery at 6 months after randomisation
measure: Small for gestational age
timeFrame: at the time of delivery at 12 months after randomisation
measure: Low birth weight
timeFrame: at birth after the completion of the first transfer
measure: Low birth weight
timeFrame: at 6 months after randomisation
measure: Low birth weight
timeFrame: at 12 months after randomisation
measure: Very low birth weight
timeFrame: at birth after the completion of the first transfer
measure: Very low birth weight
timeFrame: at 6 months after randomisation
measure: Very low birth weight
timeFrame: at 12 months after randomisation
measure: High birth weight
timeFrame: at birth after the completion of the first transfer
measure: High birth weight
timeFrame: at 6 months after randomisation
measure: High birth weight
timeFrame: at 12 months after randomisation
measure: Very high birth weight
timeFrame: at birth after the completion of the first transfer
measure: Very high birth weight
timeFrame: at 6 months after randomisation
measure: Very high birth weight
timeFrame: at 12 months after randomisation
measure: Congenital anomaly
timeFrame: At 6 months after randomisation
measure: Congenital anomaly
timeFrame: At birth after the completion of the first transfer
measure: Congenital anomaly
timeFrame: At 12 months after randomisation
measure: Admission to NICU
timeFrame: 7 days after delivery after the completion of the first transfer
measure: Admission to NICU
timeFrame: At 6 months after randomisation
measure: Admission to NICU
timeFrame: At 12 months after randomisation
measure: Genetic and epigenetic analysis of newborn
timeFrame: 1 day (Prior to the initiation of IVF/IVM) and 1 day ( at the time of delivery)
measure: Cost-effectiveness
timeFrame: Two year after randomization
Locations:
city: Ho Chi Minh City
country: Vietnam
facility: Mỹ Đức Hospital
state: Tan Binh
Study officials:
affiliation: Mỹ Đức Hospital
name: Lan N Vuong, MD,PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Vuong LN, Ho VNA, Ho TM, Dang VQ, Phung TH, Giang NH, Le AH, Pham TD, Wang R, Smitz J, Gilchrist RB, Norman RJ, Mol BW. In-vitro maturation of oocytes versus conventional IVF in women with infertility and a high antral follicle count: a randomized non-inferiority controlled trial. Hum Reprod. 2020 Nov 1;35(11):2537-2547. doi: 10.1093/humrep/deaa240.
citation: Vuong LN, Ho VNA, Ho TM, Dang VQ, Phung TH, Giang NH, Le AH, Pham TD, Wang R, Norman RJ, Smitz J, Gilchrist RB, Mol BW. Effectiveness and safety of in vitro maturation of oocytes versus in vitro fertilisation in women with high antral follicle count: study protocol for a randomised controlled trial. BMJ Open. 2018 Dec 9;8(12):e023413. doi: 10.1136/bmjopen-2018-023413.