In Vitro Fertilisation Versus Intracytoplasmic Sperm Injection in Patients Without Severe Male Factor Infertility (INVICSI)

• ClinicalTrials.gov Identifier: NCT04128904
• Recruitment Status: Recruiting
• First Posted: October 16, 2019
• Last Update Posted: August 4, 2022
• Sponsor: Copenhagen University Hospital, Hvidovre
• Information provided by (Responsible Party): Nina la Cour Freiesleben, Copenhagen University Hospital, Hvidovre

Study Description

Brief Summary:

Over recent decades, the use of intracytoplasmic sperm injection (ICSI) has increased, even among patients without severe male factor infertility. Despite the increasing use, there is no evidence to support that ICSI results in a higher live birth rate compared to conventional in vitro fertilisation (IVF) in cases without severe male factor infertility. The primary objective of this trial is to determine whether ICSI is superior to standard IVF in patients without severe male factor infertility. The primary outcome measure is live birth rate.

A total of 824 participants with infertility without severe male factor will be included in the study and allocated randomly into two groups (IVF or ICSI). The main inclusion criteria for the women are age 18-42 years, normal to slightly decreased male partner sperm/ use of donor sperm and no prior fertility treatment. In addition to live birth rate, outcome measures include fertilisation rate, total fertilisation failure, embryo quality, clinical pregnancy, miscarriage rate, preterm delivery, birth weight and congenital anomalies of the child.

The study will be performed in accordance with the ethical principles in the Helsinki Declaration. The study is approved by the Scientific Ethical Committee of the Capital Region of Denmark and the Knowledge Centre on Data Protection Compliance. Study findings will be presented in international conferences and submitted for publication in peer-reviewed journals.

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

Detailed Description:

Background

All over the world the use of intracytoplasmic sperm injection (ICSI) with the injection of a single spermatozoon into an oocyte has gradually increased since the first report of an ICSI conceived child more than 25 years ago (Palermo et al. 1992). The latest reports from the European Society of Human Reproduction and Embryology (ESHRE) and The International Committee Monitoring Assisted Reproductive Technologies (ICMART) show that standard IVF is now used in one-third of fresh assisted reproductive technology (ART) cycles, whereas ICSI accounts for as much as two-thirds of the cycles (Dyer et al. 2016, Calhaz-Jorge et al. 2017). ICSI was initially used in fertility treatment with severe male factor infertility. However, over the years a shift towards using ICSI for other indications such as unexplained infertility, mixed factor infertility or mild male factor infertility has happened (Boulet et al., 2015; Dyer et al., 2016). Today, there is no clear evidence that using ICSI over conventional IVF in cases with non-male factor infertility yields better results (van Rumste et al., 2003). In a randomised controlled trial (RCT) from 2001 including 415 couples, better fertilisation and implantation rates after conventional IVF compared to ICSI was reported (Bhattacharya et al., 2001). In contrast, another earlier prospective study including 35 women age 21-44 years, found a better fertilisation rate after ICSI compared to sibling oocytes treated with standard IVF (Khamsi et al., 2001). A retrospective study including 745 women with non-male factor infertility reported no advantage of ICSI over conventional IVF in women aged 40 years or older (Tannus et al., 2017). In line with this, so-called poor responders with a single oocyte retrieved was shown to have similar reproductive outcomes after IVF and ICSI in a retrospective study from 2015 (Sfontouris et al., 2015). RCTs comparing outcomes after IVF and ICSI in couples/women in fertility treatment with other indications than severe male factor infertility and with live birth rate as the primary endpoint are entirely missing. Despite this, the use of ICSI in this population continuous to increase.

Therefore, a carefully designed RCT to determine whether ICSI results in higher live birth rates compared with standard IVF in patients without severe male factor infertility is warranted.

Methods

Study design:

This study is a multicentre, randomised, controlled trial with six public fertility clinics in Denmark participating. All clinics are part of a university hospital setting and all hospitals perform standardised treatments according to the public health care system in Denmark.

Participants:

All women referred for their first fertility treatment at four public fertility clinics in Denmark will be screened for eligibility. Please see criteria for eligible patients under "Eligibility".

Screening and inclusion:

Patients who are potentially eligible will receive verbal and written information about the study by the investigators during their first consultation in the fertility clinic. Inclusion and randomisation of participants to either ICSI or conventional IVF will take place after the ovulation trigger has been prescribed and before the IVF/ICSI procedure. Women/couples who wish to participate in the trial are asked to sign an informed consent form prior to enrolment. They will have a minimum of two days between receiving the information and deciding whether they wish to participate in the study or not.

Randomisation and data management:

An independent statistician has prepared a computer-generated randomisation scheme in a I:I ratio between the two arms (IVF and ICSI) ensuring concealment of treatment allocation. Permuted blocks of variable size between 4 and 12 are used for randomisation. The randomisation scheme is stratified by fertility clinic and age (three age groups: 18-25, 26-37 and 38-41) to ensure that the number of participants receiving IVF and ICSI is closely balanced within each stratum.

A designated physician or nurse from each study site is appointed. The appointed nurse/physician obtains the allocation of new patients being enrolled on their trial site. The allocation is obtained in the online platform REDCap which is also used for data collection during the study. The REDCap database has a complete audit trail and is based on anonymous subject ID numbers used in the trial.

Statistical analysis:

ITT analysis and per-protocol analysis will be performed. Baseline characteristics and outcomes will be compared using t-test, Mann-Whitney U test or chi-square tests for continuous and categorical variables or logistic regression analysis, controlling for possible confounding effects where appropriate. P-values of ≤ 0.05 will be considered statistically significant. Statistical analyses will be performed by an investigator together with statistical experts. The primary RCT analysis will be performed by an independent statistician blinded to group allocation.

Sample size calculation:

The rate of first live births after transfer of up to all of the transferable embryos from the first OPU is set to 45% in the conventional IVF group and 55 % in the ICSI group. This is a superiority trial with a power of 80% and a 2-sided p-value of 5%. The sample size is estimated to be 392 patients in each group. Post-randomization exclusion is expected to be 5%, resulting in a total of 824 patients.

Intervention:

The participants will receive conventional IVF or ICSI treatment as determined by randomisation. Both treatments are part of standard treatment regimens at the trial sites.

The fertility treatment:

The women have been treated in either a short gonadotropin-releasing hormone (GnRH)-antagonist protocol or a long GnRH-agonist protocol for ovarian stimulation. Both the controlled ovarian stimulation, transvaginal ultrasound examinations and the ovulation triggering are done according to the usual daily practice at the trial sites with ovulation trigger prescribed when a minimum of two to three follicles measure 17 mm or more. Women with only one mature follicle may also be prescribed the ovulation trigger.

OPU is performed 36±2 hours after the ovulation trigger is administered. Oocyte insemination will be IVF or ICSI according to randomisation, using established procedures at the trial sites. However, short time insemination in the IVF arm is not allowed. Embryo culture and luteal phase support will follow the usual procedures at each trial site. Blastocyst transfer is performed on day 5. Patients with a poor ovarian reserve and few oocytes retrieved (≤4) are allowed transfer day 2 or 3 according to clinical practice. Single embryo transfers are planned. Surplus blastocysts of good quality are vitrified on day 5 or 6. Transfer and cryopreservation are done according to usual practice at each trial site. In cases with total freeze of all blastocysts due to the risk of ovarian hyperstimulation syndrome (OHSS), women are not excluded from the trial. In cases where all blastocysts or spare blastocysts are vitrified these are transferred in subsequent FET cycles according to the daily practice at each trial site (i.e., natural cycles, substituted or stimulated FET cycles).

Urine pregnancy test or a serum pregnancy test is done 11-16 days after embryo transfer. If pregnancy is achieved, a transvaginal ultrasound scan is performed at pregnancy week 7-9 to confirm an ongoing and intrauterine pregnancy.

Women will be asked to inform the clinic of the result of the pregnancy as is the usual procedure in the clinic.

Outcomes:

Please see "Outcome measures".

Side effects / risks:

Both IVF and ICSI are routinely used in the clinic for fertilising the oocytes. The risk of poor or no fertilisation of the oocytes exists for both IVF and ICSI. Since both fertilisation methods are a part of standard treatment in the fertility clinics, the risk for study participants is not considered higher compared with patients who do not participate in the study.

Ethics and approvals:

The study will be performed in accordance with the ethical principles in the Helsinki Declaration.

For approvals please see "Oversight".

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 824 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: In Vitro Fertilisation Versus Intracytoplasmic Sperm Injection in Patients Without Severe Male Factor Infertility (INVICSI): a Randomised, Controlled, Multicentre Trial
• Actual Study Start Date: November 29, 2019
• Estimated Primary Completion Date: December 2023
• Estimated Study Completion Date: December 2024

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Standard in vitro fertilisation (IVF); Oocytes are fertilised with standard IVF. For details please see "Project Description".	Procedure: IVF; Fertilisation with standard in vitro fertilisation (IVF). For details please see "Project Description".
Active Comparator: Intracytoplasmic sperm injection (ICSI); Oocytes are fertilised with ICSI. For details please see "Project Description".	Procedure: ICSI; Fertilisation with intracytoplasmic sperm injection (ICSI). For details please see "Project Description".

Outcome Measures

Primary Outcome Measures :

1. First live birth episode of a study cycle [ Time Frame: Minimum follow-up time is one year after inclusion ]
   The first live birth from the oocyte collection. Includes transfer of fresh embryos and frozen-thawed embryos.

Secondary Outcome Measures :

1. Fertilisation rate [ Time Frame: 16-20 hours after IVF/ICSI ]
   Fertilisation rate per aspirated oocyte retrieved. Defined as the appearance of 2 pronuclei (PN)
2. Total fertilisation failure [ Time Frame: 16-20 hours after IVF/ICSI ]
   Cycles with total fertilisation failure
3. Embryo quality [ Time Frame: Up to six days after oocyte pick-up ]
   Good quality blastocysts according to Gardner classification
4. Time-lapse kinetics [ Time Frame: Minimum follow-up time is one year after inclusion ]
   Embryo time-lapse kinetics including cleavage patterns
5. Embryo utilisation rate [ Time Frame: Up to six days after oocyte pick-up ]
   Number of transferred + cryopreserved embryos per number of 2 PN zygotes
6. Cryopreservation [ Time Frame: Up to six days after oocyte pick-up ]
   Number of cryopreserved blastocysts
7. Positive pregnancy test [ Time Frame: 11-21 days after embryo transfer ]
   Positive urine or serum hCG
8. Multiple pregnancy [ Time Frame: Up to 12 weeks after embryo transfer ]
   Number of intrauterine gestations
9. Ongoing pregnancy per transfer [ Time Frame: In gestational week 7-8 ]
   Fetal heartbeat on ultrasound
10. Cumulative pregnancy rates [ Time Frame: Minimum follow-up time is one year after inclusion ]
    The totality of clinical pregnancies following successive treatments. This includes transfer of fresh embryos and up to all cryopreserved-thawed embryos from the first stimulation cycle if pregnancy is not achieved by the initial fresh transfer.
11. Biochemical pregnancy [ Time Frame: 11-21 days after embryo transfer ]
    Positive urine or serum hCG without any clinical signs of intra- or extrauterine pregnancy
12. Pregnancy loss rate [ Time Frame: Minimum follow-up time is one year after inclusion ]
    Spontaneous or planned abortions
13. PUL [ Time Frame: Minimum follow-up time is one year after inclusion ]
    Pregnancy of unknown location
14. Ectopic pregnancy [ Time Frame: Minimum follow-up time is one year after inclusion ]
    Pregnancy outside the uterus
15. Preterm delivery [ Time Frame: Minimum follow-up time is one year after inclusion ]
    Delivery before gestational week 37.
16. Birth weight /weight for gestational age. [ Time Frame: Minimum follow-up time is one year after inclusion ]
    Weight of the baby
17. Congenital anomaly [ Time Frame: Minimum follow-up time is one year after inclusion ]
    Diagnosed congenital anomalies. Diagnosed at birth.
18. All live birth episodes [ Time Frame: Minimum follow-up time is one year after inclusion ]
    All live births from the study oocyte collection including second and further live births
19. Biochemical pregnancy [ Time Frame: Minimum follow-up time is one year after inclusion ]
    Positive urine or serum hCG 11-21 days after embryo transfer without any clinical signs of intra- or extrauterine pregnancy

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 42 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Women 18-42 years of age (both included) at the beginning of the ovarian stimulation
• BMI 18-35 kg/m2
• Indication for IVF due to tubal factor infertility, unexplained infertility, PCOS or light to moderate decreased semen quality
• Women treated with gonadotrophin in a standard short or long protocol and receiving ovulation trigger for oocyte pick up
• First treatment cycle for the couple
• Male partner with normal or non-severely decreased sperm parameters, where the sperm sample (purified) on the day of oocyte pick up is expected to contain a minimum of 2 million/mL progressive motile spermatozoa. Alternatively use of donorsperm.
• Willing to sign the informed consent

Exclusion Criteria:

• Ovarian cysts >4 cm
• Known liver or kidney disease
• Previous IVF or ICSI treatment with current partner
• Use of donor oocytes or frozen oocytes
• Unregulated thyroid disease
• Endometriosis stage 3-4
• Hypogonadotropic hypogonadism
• Severe comorbidity (e.g. diabetes or cardiovascular disease)
• Not speaking / understanding Danish or English language
• Not willing to sign the informed consent

Contacts and Locations

Contacts

Contact: Nina la Cour Freiesleben, PhD; +45 38625414; nina.la.cour.freiesleben@regionh.dk

Locations

Denmark

The Fertility Clinic, Rigshospitalet, Copenhagen University Hospital; Recruiting

Copenhagen, Denmark, 2100

Contact: Anja Pinborg, DMSc

The Fertility Clinic, Herlev Hospital, Copenhagen University Hospital; Active, not recruiting

Herlev, Denmark, 2730

The Fertility Clinic, Nordsjællands Hospital, Hillerød; Recruiting

Hillerød, Denmark, 3400

Contact: Lars Franch Andersen, PhD

The Fertility Clinic, the Reginal Hospital Horsens; Recruiting

Horsens, Denmark

Contact: Ulla B. Knudsen, PhD

The Fertility Clinic, Hvidovre Hospital, Copenhagen University Hospital; Recruiting

Hvidovre, Denmark, 2650

Contact: Nina la Cour Freiesleben, PhD +4538625414 nina.la.cour.freiesleben@regionh.dk

Contact: Sine Berntsen, MD +4538623281

The Fertility Clinic, Zealand University Hospital; Recruiting

Køge, Denmark

Contact: Anne Lis E. Mikkelsen, DMSc

Sponsors and Collaborators

Copenhagen University Hospital, Hvidovre

Investigators

• Principal Investigator: Nina la Cour Freiesleben, ph.d.; The Fertility Clinic, Hvidovre Hospital, Copenhagen University Hospital

More Information

Publications:

Palermo G, Joris H, Devroey P, Van Steirteghem AC. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet. 1992 Jul 4;340(8810):17-8. doi: 10.1016/0140-6736(92)92425-f.

Dyer S, Chambers GM, de Mouzon J, Nygren KG, Zegers-Hochschild F, Mansour R, Ishihara O, Banker M, Adamson GD. International Committee for Monitoring Assisted Reproductive Technologies world report: Assisted Reproductive Technology 2008, 2009 and 2010. Hum Reprod. 2016 Jul;31(7):1588-609. doi: 10.1093/humrep/dew082. Epub 2016 May 20.

European IVF-monitoring Consortium (EIM); European Society of Human Reproduction and Embryology (ESHRE), Calhaz-Jorge C, De Geyter C, Kupka MS, de Mouzon J, Erb K, Mocanu E, Motrenko T, Scaravelli G, Wyns C, Goossens V. Assisted reproductive technology in Europe, 2013: results generated from European registers by ESHRE. Hum Reprod. 2017 Oct 1;32(10):1957-1973. doi: 10.1093/humrep/dex264.

Boulet SL, Mehta A, Kissin DM, Warner L, Kawwass JF, Jamieson DJ. Trends in use of and reproductive outcomes associated with intracytoplasmic sperm injection. JAMA. 2015 Jan 20;313(3):255-63. doi: 10.1001/jama.2014.17985.

van Rumste MM, Evers JL, Farquhar CM. Intra-cytoplasmic sperm injection versus conventional techniques for oocyte insemination during in vitro fertilisation in patients with non-male subfertility. Cochrane Database Syst Rev. 2003;(2):CD001301. doi: 10.1002/14651858.CD001301.

Bhattacharya S, Hamilton MP, Shaaban M, Khalaf Y, Seddler M, Ghobara T, Braude P, Kennedy R, Rutherford A, Hartshorne G, Templeton A. Conventional in-vitro fertilisation versus intracytoplasmic sperm injection for the treatment of non-male-factor infertility: a randomised controlled trial. Lancet. 2001 Jun 30;357(9274):2075-9. doi: 10.1016/s0140-6736(00)05179-5.

Khamsi F, Yavas Y, Roberge S, Wong JC, Lacanna IC, Endman M. Intracytoplasmic sperm injection increased fertilization and good-quality embryo formation in patients with non-male factor indications for in vitro fertilization: a prospective randomized study. Fertil Steril. 2001 Feb;75(2):342-7. doi: 10.1016/s0015-0282(00)01674-5.

Tannus S, Son WY, Gilman A, Younes G, Shavit T, Dahan MH. The role of intracytoplasmic sperm injection in non-male factor infertility in advanced maternal age. Hum Reprod. 2017 Jan;32(1):119-124. doi: 10.1093/humrep/dew298. Epub 2016 Nov 16.

Sfontouris IA, Kolibianakis EM, Lainas GT, Navaratnarajah R, Tarlatzis BC, Lainas TG. Live birth rates using conventional in vitro fertilization compared to intracytoplasmic sperm injection in Bologna poor responders with a single oocyte retrieved. J Assist Reprod Genet. 2015 May;32(5):691-7. doi: 10.1007/s10815-015-0459-5. Epub 2015 Mar 11.

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

Berntsen S, Nohr B, Grondahl ML, Petersen MR, Andersen LF, Englund AL, Knudsen UB, Praetorius L, Zedeler A, Nielsen HS, Pinborg A, Freiesleben NC. In vitro fertilisation (IVF) versus intracytoplasmic sperm injection (ICSI) in patients without severe male factor infertility: study protocol for the randomised, controlled, multicentre trial INVICSI. BMJ Open. 2021 Jun 24;11(6):e051058. doi: 10.1136/bmjopen-2021-051058.

• Responsible Party: Nina la Cour Freiesleben, Chief Consultant, Ph.D., Clinical Associate Professor, Copenhagen University Hospital, Hvidovre
• ClinicalTrials.gov Identifier: NCT04128904
• Other Study ID Numbers: INVICSI2019
• First Posted: October 16, 2019
• Last Update Posted: August 4, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

All the individual participant data collected during the trial will be shared after deidentification upon request.

Study protocol, Statistical analysis plan, informed consent forms, clinical study report and analytic code will be available upon request.

Data will be available from 3 months following first publication and ending 5 years after the study has been concluded.

Individual participant data will be shared with researches who provide a methodologically sound proposal and whose proposed use of the data has been approved by an independent review committee.

• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: Data will be available from 3 months following first publication and ending 5 years after the study has been concluded.
• Access Criteria: Individual participant data will be shared with researches who provide a methodologically sound proposal and whose proposed use of the data has been approved by an independent review committee.

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

Keywords provided by Nina la Cour Freiesleben, Copenhagen University Hospital, Hvidovre:

Infertility; Non-male factor infertility; In vitro fertilisation (IVF); Intracytoplasmic sperm injection (ICSI); Assisted reproductive technologies (ART); Live birth rate; Reproductive outcome

Additional relevant MeSH terms:

Infertility