ICSI Versus Conventional IVF in Non-male Factor Couples

• ClinicalTrials.gov Identifier: NCT03428919
• Recruitment Status: Completed
• First Posted: February 12, 2018
• Last Update Posted: October 9, 2020
• Sponsor: Mỹ Đức Hospital
• Collaborator: An Sinh Hospital
• Information provided by (Responsible Party): Mỹ Đức Hospital

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Infertility	Procedure: ICSI; Procedure: IVF	Not Applicable

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1064 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The Effectiveness of Intracytoplasmic Sperm Injection Versus Conventional in Vitro Fertilization in Couples With Non-male Factor Infertility: a Randomized Controlled Trial
• Actual Study Start Date: March 16, 2018
• Actual Primary Completion Date: August 1, 2020
• Actual Study Completion Date: August 12, 2020

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Intracytoplasmic Sperm Injection (ICSI); All patients will be treated with a GnRH antagonist protocol. hCG (Ovitrelle 250 mg) will be used in the presence of at least three leading follicles of 17 mm. In women with ≥15 follicles ≥12 mm, 0,2 mg Triptorelin (Diphereline) will be used when there is at least two leading follicles of 17 mm. Oocyte retrieval will be performed 36 hours after triggering. 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. Fertilization check will be performed at period of 16-18 hours after insemination. 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.	Procedure: ICSI; 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.
Active Comparator: In Vitro Fertilization (IVF); All patients will be treated with a GnRH antagonist protocol. hCG (Ovitrelle 250 mg) will be used in the presence of at least three leading follicles of 17 mm. In women with ≥15 follicles ≥12 mm, 0,2 mg Triptorelin (Diphereline) will be used when there is at least two leading follicles of 17 mm. Oocyte retrieval will be performed 36 hours after triggering. Insemination will be performed by conventional IVF. Two hours after retrieval, collected OCCs will be inseminated for another 2 hours (100,000 motile sperm/ml). Inseminated OCCs will be cultured overnight in culture medium. Fertilization check will be performed at period of 16-18 hours after insemination. Embryo transfer will be performed on day 3. A maximum of 2 embryos will be transferred. The remaining grade 1-2 embryos will be frozen.	Procedure: IVF; In 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.

Outcome Measures

Primary Outcome Measures :

1. Ongoing pregnancy resulting in live birth after the first embryo transfer of the started treatment cycle. [ Time Frame: At 12 weeks of gestation ]

   Live birth is defined as the birth of at least one newborn after 24 weeks' gestation that exhibits any sign of life (twin will be a single count).

   For the timing of this occur, ongoing pregnancy will be used, conditional on the fact that this ongoing pregnancy results in live birth.

Secondary Outcome Measures :

1. Fertilization rate per oocyte inseminated/injected [ Time Frame: At 16-18 hours after injected or 17-19 hours after inseminated ]
   Fertilization is defined as the appearance of 2 PN
2. Fertilization rate per oocyte retrieved [ Time Frame: At 16-18 hours after injected or 17-19 hours after inseminated ]
   Fertilization is defined as the appearance of 2 PN
3. Abnormal fertilization rate [ Time Frame: At 16-18 hours after injected or 17-19 hours after inseminated ]
   Abnormal fertilization is defined as the appearance of 1PN or ≥3 PN
4. Total fertilization failure rate [ Time Frame: At 16-18 hours after injected or 17-19 hours after inseminated ]
   Total fertilization is defined as the absence of any zygotes with 2PN
5. Number of embryos on day 3 [ Time Frame: 3 days after oocytes pick-up day in IVF/ICSI ]
   Number of embryos on day 3
6. Number of good quality embryo on day 3 [ Time Frame: 3 days after oocytes pick-up day in IVF/ICSI ]
   Numbers of embryos on day 3 with good quality
7. Number of embryo freezing on day 3 [ Time Frame: 3 days after oocytes pick-up day in IVF/ICSI ]
   Number of embryos freezing on day 3
8. Positive pregnancy test [ Time Frame: 14 days after embryo transfer ]
   Positive pregnancy test is defined as a serum human chorionic gonadotropin level greater than 25 mIU/mL after the completion of the first transfer
9. Clinical pregnancy [ Time Frame: At 7 weeks' gestation ]
   Clinical pregnancy is defined as the presence of at least one gestational sac on ultrasound at 7 weeks' gestation with the detection of heart beat activity, after the completion of the first transfer
10. Implantation rate [ Time Frame: At 3 weeks after embryo transferred ]
    Implantation rate is defined as the number of gestational sacs per number of embryos transferred after the completion of the first transfer
11. Ongoing pregnancy [ Time Frame: At 12 weeks' gestation ]
    Ongoing pregnancy is defined as pregnancy with detectable heart rate at 12 weeks' gestation or beyond, after the completion of the first transfer
12. Cumulative ongoing pregnancy [ Time Frame: 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. ]
    Ongoing pregnancy is defined as pregnancy with detectable heart rate at 12 weeks' gestation or beyond, after transfer of all embryos from the started treatment cycle.
13. Ongoing pregnancy resulting in live birth obtained from all embryos from the first started treatment cycle [ Time Frame: 12 weeks of gestation at 12 months after randomization ]
    Live birth is defined as the birth of at least one newborn after 24 weeks' gestation that exhibits any sign of life (twin will be a single count).
14. Time from randomization to ongoing pregnancy [ Time Frame: 12 weeks of gestation after the completion of first transfer ]
    Time from randomization to ongoing pregnancy after the completion of the first transfer
15. Ovarian hyperstimulation syndrome (OHSS) [ Time Frame: At 10 days after hCG injection and 14 days after embryo transfer ]
    Symptoms of OHSS
16. Ectopic pregnancy [ Time Frame: At 12 weeks of gestation after the completion of the first transfer ]
    A pregnancy in which implantation takes place outside the uterine cavity after completion of the first transfer
17. Ectopic pregnancy [ Time Frame: At 12 weeks of gestation at 12 months after randomization. ]
    A pregnancy in which implantation takes place outside the uterine cavity after transfer of all embryos from the started treatment cycle.
18. Miscarriage [ Time Frame: At 24 weeks of gestation after the completion of the first transfer ]
    The loss of a clinical pregnancy at 24 weeks of gestation after the completion of the first transfer
19. Miscarriage [ Time Frame: At 24 weeks of gestation at 12 months after the randomization. ]
    The loss of a clinical pregnancy at 24 weeks of gestation after the completion transfer of all embryos from the started treatment cycle
20. Multiple pregnancy [ Time Frame: 7 weeks' gestation after the completion of the first transfer ]
    Multiple pregnancy is explained as two or more gestational sacs or positive heart beats by transvaginal sonography, after the completion of the first transfer
21. Multiple pregnancy [ Time Frame: 7 weeks' gestation at 12 months after randomization ]
    Multiple pregnancy is explained as two or more gestational sacs or positive heart beats by transvaginal sonography, after the completion transfer of all embryos from the started treatment cycle
22. Multiple delivery [ Time Frame: At birth, after the completion of the first transfer ]
    Multiple delivery is defined as birth of more than one baby beyond 24 weeks, after the completion of the first transfer
23. Multiple delivery [ Time Frame: At birth at 12 months after randomization ]
    Multiple delivery is defined as birth of more than one baby beyond 24 weeks, after the completion transfer of all embryos from the started treatment cycle
24. Gestational diabetes mellitus [ Time Frame: At 24 weeks of gestation after the completion of the first transfer ]
    Development of diabetes during pregnancy
25. Gestational diabetes mellitus [ Time Frame: At 24 weeks of gestation at 12 months after randomization ]
    Development of diabetes during pregnancy
26. Hypertensive disorders of pregnancy [ Time Frame: From 20 weeks of gestation up to at birth after the completion of the first transfer ]
    Hypertensive disorders of pregnancy will include pregnancy induced hypertension (PIH); pre-eclampsia (PET) and eclampsia)
27. Hypertensive disorders of pregnancy [ Time Frame: From 20 weeks of gestation up to at birth at 12 months after randomization ]
    Hypertensive disorders of pregnancy will include pregnancy induced hypertension (PIH); pre-eclampsia (PET) and eclampsia)
28. Antepartum haemorrhage [ Time Frame: From 20 weeks of gestation up to at birth, after the completion of the first transfer ]
    Including placenta previa, placenta accreta and unexplained
29. Antepartum haemorrhage [ Time Frame: From 20 weeks of gestation up to at birth, at 12 months after randomization ]
    Including placenta previa, placenta accreta and unexplained
30. Gestational age at delivery [ Time Frame: At birth, after the completion of the first transfer ]
    Gestational age at delivery
31. Gestational age at delivery [ Time Frame: At birth, at 12 months after randomization ]
    Gestational age at delivery
32. Preterm delivery [ Time Frame: At birth, after the completion of the first transfer ]
    Preterm delivery is defined as any delivery at <24, <28, <32, <37 completed weeks' gestation
33. Preterm delivery [ Time Frame: At birth, at 12 months after randomization ]
    Preterm delivery is defined as any delivery at <24, <28, <32, <37 completed weeks' gestation
34. Spontaneous preterm birth [ Time Frame: At birth, after the completion of the first transfer ]
    Spontaneous preterm birth is defined as delivery spontaneously at <24, <28, <32, <37 completed weeks
35. Spontaneous preterm birth [ Time Frame: At birth, at 12 months after randomization ]
    Spontaneous preterm birth is defined as delivery spontaneously at <24, <28, <32, <37 completed weeks
36. Iatrogenic preterm birth [ Time Frame: At birth, after the completion of the first transfer ]
    Iatrogenic preterm birth is defined as delivery non-spontaneously at <24, <28, <32, <37 completed weeks
37. Iatrogenic preterm birth [ Time Frame: At birth, at 12 months after randomization ]
    Iatrogenic preterm birth is defined as delivery non-spontaneously at <24, <28, <32, <37 completed weeks
38. Birth weight [ Time Frame: At birth, after the completion of the first transfer ]
    Weight of newborn
39. Birth weight [ Time Frame: At birth, at 12 months after randomization ]
    Weight of newborn
40. Low birth weight [ Time Frame: At birth, after the completion of the first transfer ]
    Low birth weight is defined as <2500 gm
41. Low birth weight [ Time Frame: At birth, at 12 months after randomization ]
    Low birth weight is defined as <2500 gm
42. Very low birth weight [ Time Frame: At birth, after the completion of the first transfer ]
    Very low birth weight is defined as <1500 gm
43. Very low birth weight [ Time Frame: At birth, at 12 months after randomization ]
    Very low birth weight is defined as <1500 gm
44. High birth weight [ Time Frame: At birth, after the completion of the first transfer ]
    High birth weight is defined as >4000 gm
45. High birth weight [ Time Frame: At birth, at 12 months after randomization ]
    High birth weight is defined as >4000 gm
46. Very high birth weight [ Time Frame: At birth, after the completion of the first transfer ]
    Very high birth weight is defined as >4500 gm
47. Very high birth weight [ Time Frame: At birth, at 12 months after randomization ]
    Very high birth weight is defined as >4500 gm
48. Large for gestational age [ Time Frame: At birth, after the completion of the first transfer ]
    Large for gestational age is defined as birth weight >90th percentile
49. Large for gestational age [ Time Frame: At birth, at 12 months after randomization ]
    Large for gestational age is defined as birth weight >90th percentile
50. Small for gestational age [ Time Frame: At birth, after the completion of the first transfer ]
    Small for gestational age is defined as birth weight <10th percentile
51. Small for gestational age [ Time Frame: At birth, at 12 months after randomization ]
    Small for gestational age is defined as birth weight <10th percentile
52. Congenital anomaly diagnosed at birth [ Time Frame: At birth, after the completion of the first transfer ]
    Any congenital anomaly will be included
53. Congenital anomaly diagnosed at birth [ Time Frame: At birth, at 12 months after randomization ]
    Any congenital anomaly will be included
54. Admission to NICU [ Time Frame: 7 days after delivery after the completion of the first transfer ]
    The admittance of the newborn to NICU
55. Admission to NICU [ Time Frame: 7 days after delivery, at 12 months after randomization ]
    The admittance of the newborn to NICU
56. Genetic and epigenetic analysis of newborn [ Time Frame: 1 day (Prior to the initiation of IVF/IVM) and 1 day ( at the time of delivery) ]
    Maternal whole blood; newborn's materials including cord blood, neonatal buccal smear, and placental tissue will be collected. Data will be collected for a supplementary analysis and will be reported in a separated paper.
57. Cost-effectiveness [ Time Frame: Two year after randomization ]
    Including direct and indirect costs; costs related to complications treatment. Cost data will be collected for a supplementary analysis and will be reported in a separated paper.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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%)

Contacts and Locations

Locations

Vietnam

Dang Q Vinh

Hochiminh city, Vietnam

Sponsors and Collaborators

Mỹ Đức Hospital

An Sinh Hospital

Investigators

• Principal Investigator: Lan N Vuong, PhD; University of Medicine and Pharmacy at Ho Chi Minh City

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

• Responsible Party: Mỹ Đức Hospital
• ClinicalTrials.gov Identifier: NCT03428919
• Other Study ID Numbers: CS/MD/17/12; CS/AS/17/10 ( Other Identifier: An Sinh Hospital )
• First Posted: February 12, 2018
• Last Update Posted: October 9, 2020
• Last Verified: October 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Mỹ Đức Hospital:

ICSI; Conventional IVF; Non-male factor

Additional relevant MeSH terms:

Infertility; Genital Diseases; Urogenital Diseases