In Vitro Fertilisation Versus Intracytoplasmic Sperm Injection in Patients Without Severe Male Factor Infertility (INVICSI)
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|ClinicalTrials.gov Identifier: NCT04128904|
Recruitment Status : Recruiting
First Posted : October 16, 2019
Last Update Posted : January 23, 2020
|First Submitted Date ICMJE||October 7, 2019|
|First Posted Date ICMJE||October 16, 2019|
|Last Update Posted Date||January 23, 2020|
|Actual Study Start Date ICMJE||November 15, 2019|
|Estimated Primary Completion Date||December 2023 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||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 ICMJE||Same as current|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||In Vitro Fertilisation Versus Intracytoplasmic Sperm Injection in Patients Without Severe Male Factor Infertility|
|Official Title ICMJE||In Vitro Fertilisation Versus Intracytoplasmic Sperm Injection in Patients Without Severe Male Factor Infertility (INVICSI): a Randomised, Controlled, Multicentre Trial|
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.
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.
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.
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.
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.
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.
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 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.
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.
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 ICMJE||Interventional|
|Study Phase ICMJE||Not Applicable|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Study Arms ICMJE||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE||Same as current|
|Estimated Study Completion Date ICMJE||December 2024|
|Estimated Primary Completion Date||December 2023 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years to 42 Years (Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Listed Location Countries ICMJE||Denmark|
|Removed Location Countries|
|NCT Number ICMJE||NCT04128904|
|Other Study ID Numbers ICMJE||INVICSI2019|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Responsible Party||Nina la Cour Freiesleben, Copenhagen University Hospital, Hvidovre|
|Study Sponsor ICMJE||Copenhagen University Hospital, Hvidovre|
|Collaborators ICMJE||Not Provided|
|PRS Account||Copenhagen University Hospital, Hvidovre|
|Verification Date||January 2020|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP