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: January 23, 2020
• Sponsor: Copenhagen University Hospital, Hvidovre
• Information provided by (Responsible Party): Nina la Cour Freiesleben, Copenhagen University Hospital, Hvidovre

Tracking Information

• First Submitted Date: October 7, 2019
• First Posted Date: October 16, 2019
• Last Update Posted Date: January 23, 2020
• Actual Study Start Date: November 15, 2019
• Estimated Primary Completion Date: December 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 15, 2019)

Cumulative live birth rate [ Time Frame: Follow-up ends one year after inclusion af the last patient. ]

The totality of live births following successive treatments in each of the two groups (IVF and ICSI). 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 or in case of freeze-all. Live birth rate is defined as the delivery of one or more living infants ≥22 weeks' gestation.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 15, 2019)

• Fertilisation rate [ Time Frame: 16-20 hours after IVF/ICSI ]
  Fertilisation rate per aspirated oocyte retrieved. Defined as the appearance of 2 pronuclei (PN)
• Total fertilisation failure [ Time Frame: 16-20 hours after IVF/ICSI ]
  Cycles with total fertilisation failure
• Embryo quality [ Time Frame: Up to six days after oocyte pick-up ]
  Good quality blastocysts according to Gardner classification
• Time-lapse kinetics [ Time Frame: Follow-up ends one year after inclusion af the last patient ]
  Embryo time-lapse kinetics including cleavage patterns
• Embryo utilisation rate [ Time Frame: Up to six days after oocyte pick-up ]
  Number of transferred + cryopreserved embryos per number of 2 PN zygotes
• Cryopreservation [ Time Frame: Up to six days after oocyte pick-up ]
  Number of cryopreserved blastocysts
• Clinical pregnancy [ Time Frame: 11-21 days after embryo transfer ]
  Positive urine or serum hCG
• Multiple pregnancy [ Time Frame: Up to 12 weeks after embryo transfer ]
  Number of intrauterine gestations
• Ongoing pregnancy per transfer [ Time Frame: In gestational week 7-8 ]
  Fetal heart beat on ultrasound
• Cumulative pregnancy rates [ Time Frame: Follow-up ends one year after inclusion af the last patient ]
  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.
• Biochemical pregnancy [ Time Frame: 11-21 days after embryo transfer ]
  Positive urine or serum hCG without any clinical signs of intra- or extrauterine pregnancy
• Miscarriage rate [ Time Frame: Follow-up ends one year after inclusion af the last patient ]
  Spontaneous or planned abortions
• PUL [ Time Frame: Follow-up ends one year after inclusion af the last patient ]
  Pregnancy of unknown location
• Ectopic pregnancy [ Time Frame: Follow-up ends one year after inclusion af the last patient ]
  Pregnancy outside the uterus
• Preterm delivery [ Time Frame: Follow-up ends one year after inclusion af the last patient ]
  Delivery before gestational week 37.
• Birth weight /weight for gestational age. [ Time Frame: Follow-up ends one year after inclusion af the last patient ]
  Weight of the baby
• Congenital anomaly [ Time Frame: Follow-up ends one year after inclusion af the last patient ]
  Diagnosed congenital anomalies. Diagnosed at birth.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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.

Seven hundred and eighty-four 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 four 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 will prepare 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 will be stratified by fertility clinic and age (three age groups: 18-25, 26-37 and 37-41) 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 will be appointed. The appointed nurse/physician will obtain the allocation of new patients being enrolled on their trial site. The allocation will be obtained in the online platform REDCap which will also be 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:

Baseline characteristics will be compared using t-test, Mann-Whitney U test or chi-square tests for continuous and categorical variables. Outcomes will be compared using logistic regression analysis, controlling for possible confounding effects. 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 cumulative live birth rate after transfer of all transferable embryos in the IVF group is set to 45%. The cumulative live birth rate after transfer of all transferable embryos in the ICSI group is set to 55%. With a power of 80% and a 2-sided p-value of 5% the sample size is estimated to 392 patients in each group, which means a total of 784 patients.

Intervention

Gonadotropin stimulation:

The women will be treated with either a short GnRH-antagonist protocol or a long GnRH-agonist protocol (ovarian stimulation). Both the controlled ovarian stimulation and the ovulation triggering is done according to the usual daily practice in the clinics. The gonadotropin dose is decided by each investigator based on the ovarian reserve as is the usual practice in the clinics. The dose may be adjusted during the stimulation if needed. Stimulation with LH or hCG preparations are allowed according to clinical evaluation.

Ovulation induction:

The ovulation trigger is prescribed when a minimum of three follicles are mature and measuring 17 mm or more. Women with only one or two mature follicles may also be prescribed the ovulation trigger if they wish to continue despite the poor response to stimulation (according to the usual practice in the clinics). The type of medicine as well as the dosage used for ovarian stimulation and as ovulation trigger will be the same for study participants and patients not participating in the study.

Transvaginal ultrasound examination during the stimulation period is performed according to the usual procedures in the clinic.

Oocyte retrieval:

Oocyte retrieval is performed 36±2 hours after the ovulation trigger is prescribed.

Semen preparation and fertilisation with IVF or ICSI:

A fresh semen sample is collected on the day of oocyte pick-up. The volume of the sample is assessed as well as the total number of spermatozoa and the number of motile spermatozoa. The semen sample is purified by gradient centrifugation. After purification the number of progressive motile, motile and non-motile sperm is assessed.

Oocytes are fertilised with either IVF or ICSI according to clinic standard procedures. For IVF short time fertilisation is not allowed.

Embryo transfer, pregnancy test and ultrasound:

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. Surplus blastocysts of good quality are vitrified on day 5 or 6 if the patient wish to have the spare embryos/blastocysts vitrified. Luteal phase support will follow the usual procedure in the clinic. The medication is bought by the patients according to general prescription rules.

Urine pregnancy test or a serum blood pregnancy test is done 11-21 days after fresh embryo transfer.

If pregnancy is achieved, a transvaginal ultrasound scan is performed at pregnancy week 7-9 to confirm that the pregnancy is ongoing and intrauterine.

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

Freeze:

In cases where all embryos/blastocysts or spare embryos/blastocysts are frozen these can be transferred in subsequent cycles according to the daily practice in each clinic (i.e., both natural cycles or substituted cycles are allowed).

In cases with total freeze of the fertilised embryos due to the risk of OHSS, women are not excluded from the trial.

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 Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Infertility

Intervention

• Procedure: IVF
  Fertilisation with standard in vitro fertilisation (IVF). For details please see "Project Description".
• Procedure: ICSI
  Fertilisation with intracytoplasmic sperm injection (ICSI). For details please see "Project Description".

Study Arms

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

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.
• 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. Review.
• 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.
• 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.
• 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. 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 15, 2019): 784
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2024
• Estimated Primary Completion Date: December 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Women 18-42 years of age (both included) at the beginning of the ovarian stimulation
• Regular natural menstrual cycle 21-35 days
• BMI 18-35 kg/m2
• Indication for IVF due to tubal factor infertility, unexplained infertility 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 sperm with a minimum concentration of 5 mill. progressive motile after purification per ml (minimum 5 mill. progressive motile spermatozoa in the diagnostic semen sample) and minimum 4 % morphological normal spermatozoa. Alternatively use of donorsperm.
• Willing to sign the informed consent

Exclusion Criteria:

• Less than 5 mill. progressive motile spermatozoa per ml in the purified diagnostic semen sample or <4 % morphological normal spermatozoa
• Ovarian cysts >4 cm
• Known liver or kidney disease
• Previous IVF or ICSI treatment
• Use of donor oocytes or frozen oocytes
• Unregulated thyroid disease
• Endometriosis stage 3-4
• Hypogonadotropic hypogonadism
• Severe comorbidity (diabetes, cardiovascular, liver or kidney disease)
• Not speaking / understanding Danish or English language
• Previous inclusion in the study
• Not willing to fulfil the inclusion criteria

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years to 42 Years (Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: Denmark

Administrative Information

• NCT Number: NCT04128904
• Other Study ID Numbers: INVICSI2019
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

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
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Supporting Materials: 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.

• Responsible Party: Nina la Cour Freiesleben, Copenhagen University Hospital, Hvidovre
• Study Sponsor: Copenhagen University Hospital, Hvidovre
• Collaborators: Not Provided

Investigators

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

• PRS Account: Copenhagen University Hospital, Hvidovre
• Verification Date: January 2020