None listed
Conditions
Brief summary
Hypothesis: Controlled ovarian hyperstimulation using conventional ovarian stimulation leads to a lower proportion of euploid embryos per patient than using mild ovarian stimulation when tested using the gold standard of 24 chromosome screening at D5-D6 of development. Primary Objective: To determine and compare the mean proportion of oocytes that develop to provide euploid vitrified blastocysts per patient resulting from conventional vs low dose stimulation protocol. Secondary Objectives: Number of euploid vitrified blastocysts per patient, number of 2PN preembryos generated, total number of embryos surviving to D5-D6 and total number of blastocysts biopsied. Quality of the oocytes generated using conventional vs. low dose stimulation protocols using mtDNA copy number. OHSS resulting in hospitalisation. Incidence of dose adjustment or cycle cancellation.
Interventions
Patients undergoing ovarian stimulation will be randomised into a mild and moderate starting dose of gonadotrophins.
Mild stimulation: 150 international units (IU) Menopur subcutaneous injection daily for 7 days starting on Day 2-3 (D2-3) of natural menstruation without oral contraceptive pill (OCP) pretreatment. Gonadotrophin-Releasing Hormone (GnRH) antagonist subcutaneous injection daily to commence Day 5 (D5) of Menopur until trigger criteria reached. Injections administered by fertility nu
Patients undergoing ovarian stimulation will be randomised into a mild and moderate starting dose of gonadotrophins. Mild stimulation: 150 international units (IU) Menopur subcutaneous injection daily for 7 days starting on Day 2-3 (D2-3) of natural menstruation without oral contraceptive pill (OCP) pretreatment. Gonadotrophin-Releasing Hormone (GnRH) antagonist subcutaneous injection daily to commence Day 5 (D5) of Menopur until trigger criteria reached. Injections administered by fertility nurse with minimum five years' experience or patient under direction of nurse. First bloods and scan Day 5 (D5) of Menopur. Alternate day bloods and scan to monitor response until trigger criteria reached (see below). No dose adjustment allowed. If >16 days follicle stimulating hormone (FSH) without meeting trigger criteria patient withdrawn from study. Patient compliance measured by monitoring remaining gonadotrophin doses from prescription. Trigger criteria: Leuprolide acetate or triptorelin acetate 0.2mg administered by subcutaneous injection to patients according to treating physician choice within 24 hours of developing 3 follicles of 17mm diameter or greater. Oocyte Pick Up (OPU): 34-38 hours after trigger. Aspirate all follicles greater than 12mm. Definition of oocyte retrieved equivalent to cumulus oocyte complexes (COCs). In vitro fertilisation/Intracytoplasmic Sperm Injection (IVF/ICSI) according to unit clinical protocols. Culture to blastocyst stage then trophectoderm biopsy at D5 or D6 all BB stage or above. Vitrify all biopsied blastocysts. Preimplantation genetic screening (PGS): Next-generation sequencing (NGS)-based preimplantation genetic screening using VeriSeq protocol as per Illumina. Transfer euploid embryos sequentially in frozen cycles with appropriate endometrial preparation. Overall duration of intervention equivalent to standard IVF cycle and will be abandoned if > 16 days FSH injections without adequate clinical response.
Sponsors
University New South Wales - Medicine
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
21 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
Female age 21- 40 years (randomised before 41st birthday) and projected normal responder based on AMH 8-25 pmol/L on Roche Elecsys measurement, BMI 18.0-35. Additional inclusion criteria include: primary diagnosis of infertility (see exclusion criteria); access to ejaculated sperm suitable for IVF/ICSI (including donor sperm; see exclusion criteria re: severe male factor infertility); trying for pregnancy >12 months before randomization; regular menstrual cycles of 24–35 days; hysterosalpingography, hysteroscopy, or transvaginal ultrasound documenting a uterus consistent with expected normal function; transvaginal ultrasound documenting presence and adequate visualization of both ovaries without evidence of abnormality; the trial cycle being the first or second COS cycle ever or the first or second COS cycle after having achieved pregnancy in a previous COS cycle.
Exclusion criteria
Those not meeting the inclusion criteria plus patients with significant pre-existing physical or mental health condition inconsistent with ART, unable to give fully informed consent to participation, requiring PGD for single gene disorders or parental chromosomal abnormalities. Additional: Women with polycystic ovaries (defined as ovarian volume > 10 mL or > 25 follicles per ovary) or endometrioma >2 cm diameter, severe male factor defined as <1million/mL total number sperm per ejaculate; poor response in a previous COS cycle, defined as either >16 days of gonadotropin stimulation, cancellation due to limited follicular response, or development of fewer than four follicles >15 mm; severe ovarian hyperstimulation syndrome (OHSS) in a previous COS cycle; history of recurrent miscarriage; current or past (up to 12 months before randomization); abuse of alcohol or drugs; intake of more than 14 units of alcohol per week during the past month or smoking more than ten cigarettes per day within 3 months before randomization. Use of adjuvants recorded and discouraged.
Outcome results
None listed