Clinical trial NCT04142190: Corifollitropin Alfa and Embryo Morphokinetics
Official title: Influence of Corifollitropin Alfa (Elonva) on Embryo Morphokinetics and Fertility Treatment Outcome
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Infertility
Keywords: follicle-stimulating hormone
embryo morphokinetics
reproductive medicine
Lead sponsor: Kinderwunsch Institut GmbH
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2019-10-29
Enrollment: 1351
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 42
Standard ages: ADULT
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Women suffering from infertility

Brief summary: The study evaluates the influence of corifollitropin alfa (Elonva) on embryo morphokinetics and fertility treatment outcome in comparison to a control group stimulated with Follitropin beta (Puregon).

Detailed description: Morphokinetic parameters of embryo development have been intensively investigated. However, little attention has been paid to the influence of ovarian stimulation on morphokinetic parameters. Gryshenko et al. found a significant difference in the fourth cell division time (t5) of embryos obtained after controlled ovarian hyperstimulation in long GnRH agonists and GnRH antagonist protocols. Furthermore, higher gonadotropin doses were found to slow down the development of the embryos.

Hence, the aim of this study is to investigate the influence of corifollitropin alfa (Elonva) on embryo morphokinetics and fertility treatment outcome in comparison to a control group stimulated with Follitropin beta (Puregon). The investigators hypothesize that there are differences in morphokinetic behavior of embryos within the different stimulation protocols.

A total of 742 embryos from 215 different patients suffering from infertility undergoing ovarian stimulation with Elonva and a total of 5148 embryos from 1136 patients undergoing ovarian stimulation with Puregon will be retrospectively analyzed. To exclude environmental factors the evaluation will distinguish between embryos cultured under 21% oxygen and embryos with reduced oxygen conditions (5% oxygen) in the embryoscope. Groups will be age and BMI matched.

All women included in the study underwent GnRH (Gonadotropin-releasing hormone) antagonist protocol controlled ovarian hyperstimulation. Patients received recombinant human follicle-stimulating hormone (Elonva; MSD Sharp \&Dohme GMBH, Puregon; MSD Sharp \& Dohme GMBH). ELONVA was administered for 7 days with subsequent administration of Puregon (MSD Sharp \& Dohme GMBH) in case of further need of stimulation. Puregon was administered for 8-10 days with dosage adaption according to age, weight, serum anti-mullerian hormone (sAMH) concentration, and hormonal status. Trans-vaginal sonography was performed after 5 days of stimulation, followed by every second day until the day of oocyte retrieval. Ultrasonographical measurement was performed using a RIC 5-9-D 4D intravaginal probe of a GE Voluson E8 BT09 ultrasound machine (both from GE Healthcare Austria GmbH). GnRH antagonist (Cetrotide, Merck KGaA) was injected to avoid premature ovulation. Triggering was initiated 35 h before oocyte retrieval, administered with 5000-10,000 IU human chorionic gonadotropin (hCG) subcutaneously (Pregnyl, N.V. Organon), with dosage adaption according to body weight of the patient.

Follicles larger than 10 mm in diameter were aspirated under sedation (Propofol, Fresenius Kabi Austria GmbH; Rapifen, Janssen-Cilag Pharma GmbH) and transvaginal ultrasound guidance (GE Healthcare Austria GmbH). Follicular fluid (FF) were examined for oocytes under constant conditions of 37 °C in an IVF workstation L24E with heating stage (K-SYSTEMS Kivex Biotec A/S). Intracytoplasmic sperm injection (ICSI) was performed on all metaphase II (MII) oocytes 4-5h after oocyte retrieval according to our standard operating procedure in both groups of patients.

After oocyte retrieval and fertilization, oocytes were cultivated in universal culture medium (Gynemed Medizinprodukte GmbH \& Co. KG, Germany). After 14-16 h, fertilization check was performed. All normal fertilized embryos with two pronuclei (PN) were then cultured using Embryoslide dishes in Embryoscope® time-lapse incubator (both Vitrolife AB, Sweden). With the built-in camera and microscope, images of the developing embryo were taken every 15 min in seven different layers. Definition of morphokinetic parameters was performed according to the criteria proposed by Ciray et al. and was analyzed with software developed for time-lapse image analysis (Embryoviewer® software; Vitrolife AB, Sweden).

Eligibility criteria: Inclusion Criteria:

* Age: 18-42
* BMI: 19-29.9
* Primary or secondary infertility
* Ovarian stimulation with Elonva/Puregon
* Embryos cultured in embryoscope

Exclusion Criteria:

* unexpected low response
* genetic testing

Primary outcomes:
measure: Time of pronuclei disappearance
timeFrame: 16-18 hours after fertilization
measure: Two discrete cells
timeFrame: 26-28 hours after fertilization
measure: Three discrete cells
timeFrame: 28-44 hours after fertilization
measure: Four discrete cells
timeFrame: 44-45 hours after fertilization
measure: Five discrete cells
timeFrame: 44-68 hours after fertilization
measure: Six discrete cells
timeFrame: 44-68 hours after fertilization
measure: Seven discrete cells
timeFrame: 44-68 hours after fertilization
measure: Eight discrete cells
timeFrame: 68-69 hours after fertilization
measure: Nine discrete cells
timeFrame: 69-92 hours after fertilization
measure: Morula stage
timeFrame: 92 hours after fertilization
Secondary outcomes:
measure: Number of oocytes retrieved
timeFrame: Number of oocytes retrieved will be evaluated after one treatment cycle (each cycle is between 28 and 35 days)
measure: Stage of oocyte development
timeFrame: Stage of oocytes retrieved will be evaluated after one treatment cycle (each cycle is between 28 and 35 days)
measure: Fertilized oocytes
timeFrame: Number of fertilized oocytes will be evaluated after one treatment cycle (each cycle is between 28 and 35 days)
measure: Embryo grading
timeFrame: The quality of embryos will be evaluated after one treatment cycle (each cycle is between 28 and 35 days)
measure: Biochemical pregnancy (measurement of beta hCG)
timeFrame: Biochemical pregnancies will be evaluated after successful implantation (1 week after embryo transfer)
measure: Life birth
timeFrame: Life births will be evaluated after successful pregnancy (9 moths after embryo transfer)
measure: Weight (kilograms)
timeFrame: Weight of the newborn will be evaluated after birth (9 moths after embryo transfer)
measure: Height (centimeters)
timeFrame: Height of the newborn will be evaluated after birth (9 moths after embryo transfer)
Other outcomes:
Locations:
city: Dobl
country: Austria
facility: Das Kinderwunsch Institut Schenk GmbH
state: Styria
Study officials:
affiliation: Das Kinderwunsch Institut Schenkg GmbH
name: Michael Schenk, Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gryshchenko MG, Pravdyuk AI, Parashchyuk VY. Analysis of factors influencing morphokinetic characteristics of embryos in ART cycles. Gynecol Endocrinol. 2014 Oct;30 Suppl 1:6-8. doi: 10.3109/09513590.2014.945763.
citation: Wissing ML, Bjerge MR, Olesen AI, Hoest T, Mikkelsen AL. Impact of PCOS on early embryo cleavage kinetics. Reprod Biomed Online. 2014 Apr;28(4):508-14. doi: 10.1016/j.rbmo.2013.11.017. Epub 2013 Dec 17.
citation: Chawla M, Fakih M, Shunnar A, Bayram A, Hellani A, Perumal V, Divakaran J, Budak E. Morphokinetic analysis of cleavage stage embryos and its relationship to aneuploidy in a retrospective time-lapse imaging study. J Assist Reprod Genet. 2015 Jan;32(1):69-75. doi: 10.1007/s10815-014-0372-3. Epub 2014 Nov 14.
citation: Armstrong S, Vail A, Mastenbroek S, Jordan V, Farquhar C. Time-lapse in the IVF-lab: how should we assess potential benefit? Hum Reprod. 2015 Jan;30(1):3-8. doi: 10.1093/humrep/deu250. Epub 2014 Oct 14.
citation: Milewski R, Kuc P, Kuczynska A, Stankiewicz B, Lukaszuk K, Kuczynski W. A predictive model for blastocyst formation based on morphokinetic parameters in time-lapse monitoring of embryo development. J Assist Reprod Genet. 2015 Apr;32(4):571-9. doi: 10.1007/s10815-015-0440-3. Epub 2015 Feb 18.
citation: VerMilyea MD, Tan L, Anthony JT, Conaghan J, Ivani K, Gvakharia M, Boostanfar R, Baker VL, Suraj V, Chen AA, Mainigi M, Coutifaris C, Shen S. Computer-automated time-lapse analysis results correlate with embryo implantation and clinical pregnancy: a blinded, multi-centre study. Reprod Biomed Online. 2014 Dec;29(6):729-36. doi: 10.1016/j.rbmo.2014.09.005. Epub 2014 Sep 21.