Clinical trial NCT03428919: ICSI Versus Conventional IVF in Non-male Factor Couples
Official title: The Effectiveness of Intracytoplasmic Sperm Injection Versus Conventional in Vitro Fertilization in Couples With Non-male Factor Infertility: a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Infertility
Keywords: ICSI
Conventional IVF
Non-male factor
Lead sponsor: Mỹ Đức Hospital
Sponsor class: OTHER
Collaborators: name: An Sinh Hospital
First posted: 2018-02-12
Enrollment: 1064
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Conventionally, ICSI was initially developed and has been shown to be an effective treatment for male factor infertility. It is increasingly being used for patients without a male factor diagnosis, despite the lack of clinical evidence to support its use. Moreover, ICSI is an invasive and expensive procedure. This multi-center, randomized, controlled, parallel-group trial will be conducted to compare the effectiveness of ICSI versus conventional IVF in infertile couples scheduled for IVF treatment, in whom the male partner has normal sperm.

Detailed description: All patients undergoing IVF/ICSI will be treated with a GnRH antagonist protocol. Recombinant FSH (Puregon, MSD) will be given on day 2 or day 3 of menstrual cycle for 5 days. The starting dose is individualized for each patient based on the following criteria: AMH \<0.7 ng/mL, dose 300 IU/day; AMH 0.7-2.1 ng/mL, dose 200 IU/day; AMH \>2.1 ng/mL, dose 150 IU/day. After that, investigators can titrate the dose based on their clinical judgment. Follicular development will be monitored by ultrasound scanning and measurement of estradiol and progesterone levels, starting on day 5 of stimulation. Scanning and hormonal measurement will be repeated every 2 to 3 days, depending on the size of follicles. An antagonist is routinely used on day 5 until the day of triggering. Criteria for triggering, by hCG (Ovitrelle 250 mg, Merck, Germany) will be the presence of at least three leading follicles of 17 mm. In women with excessive follicular response (≥15 follicles ≥12 mm), 0,2 mg Triptorelin (Diphereline, Ipsen Beaufour, France) will be used when there are at least two leading follicles of 17 mm. Oocyte retrieval will be performed 36 hours after triggering.

Randomization and allocation of participants to study groups will be performed on the day of egg pick up, after having obtained the semen from the husband. Eligible participants that have provided informed consent will be randomised to either ICSI or conventional IVF.

In ICSI group, insemination will be performed by using ICSI, 3 - 4 hours after oocyte retrieval. OCCs will be stripped by using hyaluronidase. Only matured oocytes will be inseminated.

In conventional IVF group, insemination will be performed by conventional IVF. Two hours after retrieval, collected OCCs will be inseminated for another 2 hours, at a concentration of 100,000 motile sperm/ml. Inseminated OCCs will be cultured overnight in culture medium.

In both groups, fertilization check will be performed under inverted microscope at period of 16-18 hours after insemination. On day 3, embryo evaluation will be performed at fixed time point 66±2 hours after fertilization, using the Istanbul consensus. Embryo transfer will be performed on day 3 under ultrasound guidance. A maximum of 2 embryos will be transferred into the uterus. The remaining grade 1 and 2 embryos will be frozen. Luteal-phase support will be done with estradiol (Valiera 2mg) 8mg/day and vaginal progesterone 800mg/day (Cyclogest 400mg) until 7th week of gestation.

If there are contra-indications for fresh embryo transfer, a freeze-all strategy will be applied, using Cryotech technique. Indications for freeze-all include: risk of ovarian hyperstimulation syndrome (OHSS), premature progesterone rise (≥1.5 ng/ml), thin endometrium (\<7 mm), fluid in cavity on day of embryo transfer, endometrial polyp, hydrosalpinx that have not removed before oocyte retrieval.

In the next cycle, endometrium will be prepared by using estradiol (Valiera 2 mg, 8 mg/day) orally, starting from day 2-3 of menstrual cycle. When the endometrium thickness reaches 8 mm or more, patients will start using progesterone vaginally (Cyclogest 400 mg, 800 mg/day). Embryo transfer will be performed 3 days after using progesterone. On the day of embryo transfer, embryos will be thawed. In the frozen/thawed cycle, the best embryos will be utilized first, as in fresh transfer. Two hours after thawing, a maximum of 2 surviving embryos will be transferred into the uterus under ultrasound guidance. Luteal phase support will be provided with estradiol (Valiera 2mg) 8mg/day and vaginal progesterone 800 mg/day (Cyclogest 400 mg) until the seventh week of gestation.

In both groups, clinicians who perform embryo transfer, either fresh or frozen cycles, will be blinded to the intervention.

A serum hCG will be measured 2 weeks after embryo transferred, and if positive, an ultrasound scan of the uterus will be performed at gestational weeks 7 and 12. At 11 - 12 weeks of gestation, participants will be referred to the Outpatient clininc, O\&G Department, My Duc hospital or An Sinh hospital for prenatal care until giving birth.

Eligibility criteria: Inclusion Criteria:

* Having ≤ 2 IVF/ICSI cycles
* Total sperm count and motility are normal (WHO, 2010)
* Antagonist protocol
* Agree to have ≤ 2 embryos transferred
* Not participating in another IVF study at the same time

Exclusion Criteria:

* In-vitro maturation (IVM) cycles
* Using frozen semen
* Poor fertilization in previous cycle (≤ 25%)

Primary outcomes:
measure: Ongoing pregnancy resulting in live birth after the first embryo transfer of the started treatment cycle.
timeFrame: At 12 weeks of gestation
Secondary outcomes:
measure: Fertilization rate per oocyte inseminated/injected
timeFrame: At 16-18 hours after injected or 17-19 hours after inseminated
measure: Fertilization rate per oocyte retrieved
timeFrame: At 16-18 hours after injected or 17-19 hours after inseminated
measure: Abnormal fertilization rate
timeFrame: At 16-18 hours after injected or 17-19 hours after inseminated
measure: Total fertilization failure rate
timeFrame: At 16-18 hours after injected or 17-19 hours after inseminated
measure: Number of embryos on day 3
timeFrame: 3 days after oocytes pick-up day in IVF/ICSI
measure: Number of good quality embryo on day 3
timeFrame: 3 days after oocytes pick-up day in IVF/ICSI
measure: Number of embryo freezing on day 3
timeFrame: 3 days after oocytes pick-up day in IVF/ICSI
measure: Positive pregnancy test
timeFrame: 14 days after embryo transfer
measure: Clinical pregnancy
timeFrame: At 7 weeks' gestation
measure: Implantation rate
timeFrame: At 3 weeks after embryo transferred
measure: Ongoing pregnancy
timeFrame: At 12 weeks' gestation
measure: Cumulative ongoing pregnancy
timeFrame: At 12 weeks' gestation at 12 months after randomization. After 12 months, most patients doing IVF have finished all their frozen embryos; therefore, we consider this time point for analyzing the cumulative ongoing pregnancy rate.
measure: Ongoing pregnancy resulting in live birth obtained from all embryos from the first started treatment cycle
timeFrame: 12 weeks of gestation at 12 months after randomization
measure: Time from randomization to ongoing pregnancy
timeFrame: 12 weeks of gestation after the completion of first transfer
measure: Ovarian hyperstimulation syndrome (OHSS)
timeFrame: At 10 days after hCG injection 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 12 weeks of gestation at 12 months after randomization.
measure: Miscarriage
timeFrame: At 24 weeks of gestation after the completion of the first transfer
measure: Miscarriage
timeFrame: At 24 weeks of gestation at 12 months after the randomization.
measure: Multiple pregnancy
timeFrame: 7 weeks' gestation after the completion of the first transfer
measure: Multiple pregnancy
timeFrame: 7 weeks' gestation at 12 months after randomization
measure: Multiple delivery
timeFrame: At birth, after the completion of the first transfer
measure: Multiple delivery
timeFrame: At birth at 12 months after randomization
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 12 months after randomization
measure: Hypertensive disorders of pregnancy
timeFrame: From 20 weeks of gestation up to at birth after the completion of the first transfer
measure: Hypertensive disorders of pregnancy
timeFrame: From 20 weeks of gestation up to at birth at 12 months after randomization
measure: Antepartum haemorrhage
timeFrame: From 20 weeks of gestation up to at birth, after the completion of the first transfer
measure: Antepartum haemorrhage
timeFrame: From 20 weeks of gestation up to at birth, at 12 months after randomization
measure: Gestational age at delivery
timeFrame: At birth, after the completion of the first transfer
measure: Gestational age at delivery
timeFrame: At birth, at 12 months after randomization
measure: Preterm delivery
timeFrame: At birth, after the completion of the first transfer
measure: Preterm delivery
timeFrame: At birth, at 12 months after randomization
measure: Spontaneous preterm birth
timeFrame: At birth, after the completion of the first transfer
measure: Spontaneous preterm birth
timeFrame: At birth, at 12 months after randomization
measure: Iatrogenic preterm birth
timeFrame: At birth, after the completion of the first transfer
measure: Iatrogenic preterm birth
timeFrame: At birth, at 12 months after randomization
measure: Birth weight
timeFrame: At birth, after the completion of the first transfer
measure: Birth weight
timeFrame: At birth, at 12 months after randomization
measure: Low birth weight
timeFrame: At birth, after the completion of the first transfer
measure: Low birth weight
timeFrame: At birth, at 12 months after randomization
measure: Very low birth weight
timeFrame: At birth, after the completion of the first transfer
measure: Very low birth weight
timeFrame: At birth, at 12 months after randomization
measure: High birth weight
timeFrame: At birth, after the completion of the first transfer
measure: High birth weight
timeFrame: At birth, at 12 months after randomization
measure: Very high birth weight
timeFrame: At birth, after the completion of the first transfer
measure: Very high birth weight
timeFrame: At birth, at 12 months after randomization
measure: Large for gestational age
timeFrame: At birth, after the completion of the first transfer
measure: Large for gestational age
timeFrame: At birth, at 12 months after randomization
measure: Small for gestational age
timeFrame: At birth, after the completion of the first transfer
measure: Small for gestational age
timeFrame: At birth, at 12 months after randomization
measure: Congenital anomaly diagnosed at birth
timeFrame: At birth, after the completion of the first transfer
measure: Congenital anomaly diagnosed at birth
timeFrame: At birth, at 12 months after randomization
measure: Admission to NICU
timeFrame: 7 days after delivery after the completion of the first transfer
measure: Admission to NICU
timeFrame: 7 days after delivery, at 12 months after randomization
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
Other outcomes:
Locations:
city: Hochiminh city
country: Vietnam
facility: Dang Q Vinh
Study officials:
affiliation: University of Medicine and Pharmacy at Ho Chi Minh City
name: Lan N Vuong, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Dang VQ, Vuong LN, Luu TM, Pham TD, Ho TM, Ha AN, Truong BT, Phan AK, Nguyen DP, Pham TN, Pham QT, Wang R, Norman RJ, Mol BW. Intracytoplasmic sperm injection versus conventional in-vitro fertilisation in couples with infertility in whom the male partner has normal total sperm count and motility: an open-label, randomised controlled trial. Lancet. 2021 Apr 24;397(10284):1554-1563. doi: 10.1016/S0140-6736(21)00535-3.
citation: Dang VQ, Vuong LN, Ho TM, Ha AN, Nguyen QN, Truong BT, Pham QT, Wang R, Norman RJ, Mol BW. The effectiveness of ICSI versus conventional IVF in couples with non-male factor infertility: study protocol for a randomised controlled trial. Hum Reprod Open. 2019 Mar 27;2019(2):hoz006. doi: 10.1093/hropen/hoz006. eCollection 2019.