Clinical trial NCT03740880: Trigger Time in Advanced Maternal Age Patients With Low AMH
Official title: Pilot Study: Optimal Trigger Time in Advanced Maternal Age Patients With Low AMH
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: the Number of Mature Oocytes
Keywords: ICSI
early trigger
poor ovarian responders
low AMH
Lead sponsor: ART Fertility Clinics LLC
Sponsor class: OTHER
First posted: 2018-11-14
Enrollment: 1
Sex: FEMALE
Minimum age (years): 40
Maximum age (years): 48
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Two groups: 1 groups of patients receiving an early trigger (14mm), the other group receiving a late trigger (17mm)
Primary purpose: DIAGNOSTIC

Brief summary: The investigators want to verify if advanced maternal age patients with a low Anti-Müllerian hormone (AMH) level may benefit from an early trigger time (compared to a late trigger).

Detailed description: During assisted reproduction, patients are stimulated in order to achieve a multifollicular development. The final step in this stimulation process is "the trigger" that will induce the final maturation of the oocytes. This timing is historically put once at least one follicle of 16-17 mm is obtained.

When looking at poor ovarian responder (POR) patients (characterized by a low AMH), the investigators observe shorter menstrual cycles and thus it is thought that the oocyte selected for ovulation, will also mature faster. This observation may indicate that POR patients potentially do not benefit from a trigger performed once a leading follicle of 17 mm is present, but rather from an earlier trigger.

The main objective is to analyse if an early trigger (leading follicle of 14 mm) results in the same maturation rate in POR patient as compared to a late trigger (17 mm). As the embryos will be cultured in a time lapse imaging system, annotations on the developmental kinetics can be made and the differences in fertilization rate and embryo development can be analysed as secondary outcome parameter. On top of this, patients will undergo a genetic testing of their embryos and this genetic analysis , together with the mtDNA copy number will also be compared between patients with early or late trigger. Euploid blastocysts will be transferred in subsequent frozen embryo transfer (FET) cycles and give an indication on the clinical outcome between IVF and ICSI.

Eligibility criteria: Inclusion Criteria:

* • POR defined according to the Bologna criteria:

  * AMA: ≥40 years and AMH \<1.1 ng/ml
  * Previous poor ovarian response with maximum 3 cumulus oocyte complexes retrieved after conventional stimulation
  * Antral follicle count \< 5-7

    * Cycling patients
    * Fresh ejaculates
    * ICSI
    * BMI 19-32 kg/m2
    * Ovarian stimulation protocol: Antagonist HMG 450 IU to ensure all receptors are covered and to ensure maximum recruitment. Dose adjustments can be made after 5 days of stimulation
    * Type of trigger for final oocyte maturation: dual trigger: 10.000 IU hCG i.m. and 0.3 mg Deca
    * Couples requesting preimplantation genetic testing (for aneuploidies) of their embryos
    * Follicular measurements should be performed at IVI RMA Fertility, Abu Dhabi, UAE: a single operator will perform the ultrasound for the final measurement before trigger. Recruitment can be done by all physicians
    * Only patients with an oral contraceptive pill (OCP) pretreatment to synchronize follicular development:
  * 2 weeks OCP followed by
  * a wash out of 5 days (without OCP) followed by

    * o start stimulation
    * Basal hormone profile (FSH, LH, E2, P4) measured between day 1-3 at IVIRMA Fertility, Abu Dhabi, UAE
  * FSH \<15 IU
  * E2 \<50 pg/ml
  * P \<1ng/ml

    * Only the Arab population
    * Oocyte retrieval: 36 hours after trigger
    * PGT-A

Exclusion Criteria:

* If follicular measurement before randomization shows a leading follicle ≥ 13mm
* IVF
* History of:

  * Endometriosis AFS\>2
  * Chemotherapy/radiotherapy
  * Ovarian surgery (iatrogenic)
  * Cyst puncture in the last three months
* Sonographic finding of:

  * Hydrosalpinx
  * Ovarian cyst
* Testicular samples and frozen ejaculates
* If patients are pre-screened at the start of stimulation but no follicular development is observed, patients will not be randomized
* Asynchronized follicular development at the moment of randomization: if the leading follicle is \>3 mm lager than the smaller follicles.
* All other hormonal pretreatments (except OCP) and all patients without hormonal pretreatment

Primary outcomes:
measure: the number of mature oocytes
timeFrame: 1 day
Secondary outcomes:
measure: Maturation rate
timeFrame: 1 day
measure: Fertilization rate
timeFrame: 1 day
measure: Embryo development up to day 3
timeFrame: 3 days
measure: Blastulation rate
timeFrame: 7 days
measure: Embryo development up to day 5
timeFrame: 7 days
measure: Morphokinetic development
timeFrame: 7 days
measure: Ploidy state: euploid or aneuploid
timeFrame: 7 days
measure: Mitoscore value: ranges from 10-1500
timeFrame: 7 days
measure: Pregnancy outcome
timeFrame: 3 months
Other outcomes:
measure: Controlled ovarian stimulation: dosage
timeFrame: 2 weeks
measure: Controlled ovarian stimulation: days of stimulation
timeFrame: 2 weeks
measure: Controlled ovarian stimulation: hormonal profile
timeFrame: 2 weeks
measure: Controlled ovarian stimulation: measurement of follicles
timeFrame: 2 weeks
measure: Mean menstrual cycle length
timeFrame: 3 months
Locations:
city: Abu Dhabi
country: United Arab Emirates
facility: IVI RMA Abu Dhabi
Study officials:
affiliation: IVIRMA Abu Dhabi
name: Neelke De Munck, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Haahr T, Esteves SC, Humaidan P. Individualized controlled ovarian stimulation in expected poor-responders: an update. Reprod Biol Endocrinol. 2018 Mar 9;16(1):20. doi: 10.1186/s12958-018-0342-1.
citation: Oudendijk JF, Yarde F, Eijkemans MJ, Broekmans FJ, Broer SL. The poor responder in IVF: is the prognosis always poor?: a systematic review. Hum Reprod Update. 2012 Jan-Feb;18(1):1-11. doi: 10.1093/humupd/dmr037. Epub 2011 Oct 10.
citation: Ferraretti AP, La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L; ESHRE working group on Poor Ovarian Response Definition. ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod. 2011 Jul;26(7):1616-24. doi: 10.1093/humrep/der092. Epub 2011 Apr 19.
citation: Beckers NG, Macklon NS, Eijkemans MJ, Fauser BC. Women with regular menstrual cycles and a poor response to ovarian hyperstimulation for in vitro fertilization exhibit follicular phase characteristics suggestive of ovarian aging. Fertil Steril. 2002 Aug;78(2):291-7. doi: 10.1016/s0015-0282(02)03227-2.