Clinical trial NCT04128904: In Vitro Fertilisation Versus Intracytoplasmic Sperm Injection in Patients Without Severe Male Factor Infertility
Official title: In Vitro Fertilisation Versus Intracytoplasmic Sperm Injection in Patients Without Severe Male Factor Infertility (INVICSI): a Randomised, Controlled, Multicentre Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Infertility
Keywords: Infertility
Non-male factor infertility
In vitro fertilisation (IVF)
Intracytoplasmic sperm injection (ICSI)
Assisted reproductive technologies (ART)
Live birth rate
Reproductive outcome
Lead sponsor: Copenhagen University Hospital, Hvidovre
Sponsor class: OTHER
First posted: 2019-10-16
Enrollment: 824
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 42
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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".

Eligibility 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

Primary outcomes:
measure: Cumulative live birth rate from first live birth episode of a study cycle
timeFrame: Minimum follow-up time is one year after inclusion
Secondary outcomes:
measure: Fertilisation rate
timeFrame: 16-20 hours after IVF/ICSI
measure: Total fertilisation failure
timeFrame: 16-20 hours after IVF/ICSI
measure: Embryo quality
timeFrame: Up to six days after oocyte pick-up
measure: Time-lapse kinetics
timeFrame: Minimum follow-up time is one year after inclusion
measure: Embryo utilisation rate
timeFrame: Up to six days after oocyte pick-up
measure: Cryopreservation
timeFrame: Up to six days after oocyte pick-up
measure: Positive pregnancy test
timeFrame: 11-21 days after embryo transfer
measure: Multiple pregnancy
timeFrame: Up to 12 weeks after embryo transfer
measure: Ongoing pregnancy per transfer
timeFrame: In gestational week 7-8
measure: Cumulative pregnancy rates
timeFrame: Minimum follow-up time is one year after inclusion
measure: Biochemical pregnancy
timeFrame: 11-21 days after embryo transfer
measure: Pregnancy loss rate
timeFrame: Minimum follow-up time is one year after inclusion
measure: PUL
timeFrame: Minimum follow-up time is one year after inclusion
measure: Ectopic pregnancy
timeFrame: Minimum follow-up time is one year after inclusion
measure: Preterm delivery
timeFrame: Minimum follow-up time is one year after inclusion
measure: Birth weight /weight for gestational age.
timeFrame: Minimum follow-up time is one year after inclusion
measure: Congenital anomaly
timeFrame: Minimum follow-up time is one year after inclusion
measure: All live birth episodes
timeFrame: Minimum follow-up time is one year after inclusion
measure: Biochemical pregnancy
timeFrame: Minimum follow-up time is one year after inclusion
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: The Fertility Clinic, Rigshospitalet, Copenhagen University Hospital
city: Herlev
country: Denmark
facility: The Fertility Clinic, Herlev Hospital, Copenhagen University Hospital
city: Hillerød
country: Denmark
facility: The Fertility Clinic, Nordsjællands Hospital, Hillerød
city: Horsens
country: Denmark
facility: The Fertility Clinic, the Reginal Hospital Horsens
city: Hvidovre
country: Denmark
facility: The Fertility Clinic, Hvidovre Hospital, Copenhagen University Hospital
city: Køge
country: Denmark
facility: The Fertility Clinic, Zealand University Hospital
Study officials:
affiliation: The Fertility Clinic, Hvidovre Hospital, Copenhagen University Hospital
name: Nina la Cour Freiesleben, ph.d.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.