Clinical trial NCT02939898: Mapping the Endocrine Determinants of Ovarian Stimulation to Optimize Outcomes in Fresh Embryo Transfer Cycles
Official title: Reducing the Impact of Ovarian Stimulation - The RIOT Project Study RIOT-B: Mapping the Endocrine Determinants of Ovarian Stimulation to Optimize Outcomes in Fresh Embryo Transfer Cycles
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Infertility
Lead sponsor: Herlev Hospital
Sponsor class: OTHER
Collaborators: name: Rigshospitalet, Denmark
name: Region Capital Denmark
name: Copenhagen University Hospital, Denmark
First posted: 2016-10-20
Enrollment: 33
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The goal of this project is to identify autocrine, paracrine and endocrine factors which are associated with intercycle variation in cyclical follicle recruitment.

Patients will be monitored in a natural cycle, a stimulated cycle and a follow up. In the stimulated cycle patients will be randomized to co-treatment with aromatase inhibitor or placebo during ovarian stimulation.

Detailed description: The primary aim of this project is to explore the putative cyclic recruitment 'gatekeeping' functions of gonadotropins, sex steroids, anti-muellarian hormone and pregnancy associated plasma protein A in normal ovulatory cycles, and the impact of ovarian stimulation on cyclic follicle recruitment in the following cycle.

It is further proposed that supra-physiological levels of estradiol and progesterone which arise from ovarian stimulation may modulate the size of the secondarily recruited follicle cohort in the next cycle. In order to explore the relative contribution of sex steroids as determinants of the size of the next cycle 'wave' of recruitment further, a second aim of this study will be investigate whether limiting the rise in sex steroid levels during ovarian stimulation, by co-treatment with aromatase inhibitor impacts on cyclic recruitment.

Eligibility criteria: Inclusion Criteria:

* Indication for IVF/ICSI treatment
* Eligible for IVF/ICSI treatment according to local criteria
* Regular cycles 21-35 days (both included)
* Age \<40 years
* AMH 8-32 (both included)
* Written consent
* Willing to undergo intensive monitoring in a natural cycle (the cycle prior to the monitored natural cycle must be hormone treatment free), stimulated cycle and follow up in the subsequent cycle

Exclusion Criteria:

* Any contraindication for IVF/ICSI treatment according to local criteria
* Previous stimulation for IVF/ICSI with \< 4 oocytes obtained
* PCOS
* Undergoing IVF/ICSI for the purpose of fertility preservation
* Allergy towards study drug

Primary outcomes:
measure: Size of follicle cohort in relation to serum endocrine and paracrine markers
timeFrame: The change in size of follicle cohort in relation to change in endocrine and paracrine markers assessed throughout the study completion, up to 3 years.
Secondary outcomes:
measure: Size of the cyclically recruited follicle cohort after ovarian stimulation with and without co-treatment with Aromatase Inhibitor.
timeFrame: The change in size of follicle cohort throughout the study completion, up to 3 years.
measure: Expression of cytokine and growth factors in endometrial secretions following co-treatment with Aromatase Inhibitor compared with placebo control.
timeFrame: Assessed in stimulated cycle at time of embryo transfer (throughout study completion, up to 3 years).
measure: Serum E2, P, Tst and Androstenedione levels
timeFrame: The change in levels throughout the study completion, up to 3 years.
measure: Area under the curve for P and 17-hydroxyprogesterone.
timeFrame: The change in levels throughout the study completion, up to 3 years.
measure: Total International Units of Follicle Stimulating Hormone used per treatment cycle.
timeFrame: Assessed throughout study completion, up to 3 years.
measure: Number of follicles > 12 mm
timeFrame: Assessed throughout the study completion, up to 3 years.
measure: Number of oocytes obtained
timeFrame: Assessed during stimulation treatment (throughout the study completion, up to 3 years).
measure: Proportion of oocytes resulting in top quality day 2, day 3 embryos or day 5/6 embryos according to validated morphological criteria.
timeFrame: Assessed during stimulation treatment (throughout the study completion, up to 3 years).
measure: Oocyte fertilization rate
timeFrame: Assessed during stimulation treatment (throughout the study completion, up to 3 years).
measure: Number and quality of embryos obtained.
timeFrame: Assessed during stimulation treatment (throughout the study completion, up to 3 years).
measure: Endometrial thickness
timeFrame: Assessed throughout the study completion, up to 3 years.
measure: Uterine contraction rate (contractions/minute)
timeFrame: Assessed throughout the study completion, up to 3 years.
measure: Implantation rate
timeFrame: Assessed during stimulation treatment (throughout the study completion, up to 3 years).
measure: Reported side effects
timeFrame: From start of stimulation and administration of study medication to pregnancy scan week gestational age 7-8. Assessed throughout the study completion, up to 3 years.
measure: Morphokinetic parameters of embryo quality as measured using a Time Lapse analysis.
timeFrame: Assessed from time of oocyte pick-up to embryo transfer following stimulation (throughout study completion, up to 3 years)
measure: Clinical pregnancy rate
timeFrame: Pregnancy scan at gestational age week 7-8 (3-4 weeks after the positive hCG in serum) Assessed during stimulation treatment (throughout the study completion, up to 3 years).
measure: Follicular fluid endocrine and paracrine markers following co-treatment with Aromatase Inhibitor compared with placebo control.
timeFrame: Assessed during stimulation treatment (throughout the study completion, up to 3 years).
measure: Biochemical pregnancy rate
timeFrame: Assessed during stimulation treatment (throughout the study completion, up to 3 years).
measure: Area under the curve for E2, P and LH
timeFrame: The change in levels throughout the study completion, up to 3 years.
Other outcomes:
Locations:
city: Herlev
country: Denmark
facility: Unit of Reproductive Medicine, Herlev Hospital
state: Capital Region
Study officials:
affiliation: Unit of Reproductive Medicine, Herlev/Gentofte Hospital
name: Sven O. Skouby, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Poulsen LC, Warzecha AK, Bulow NS, Bungum L, Macklon NS, Yding Andersen C, Skouby SO. Effects of letrozole cotreatment on endocrinology and follicle development in women undergoing ovarian stimulation in an antagonist protocol. Hum Reprod. 2022 Jun 30;37(7):1557-1571. doi: 10.1093/humrep/deac119.
citation: Dreyer Holt M, Warzecha AK, Bulow NS, Skouby SO, Englund ALM, Birch Petersen K, Macklon NS. Does adjuvant letrozole reduce uterine peristalsis prior to fresh embryo transfer? Hum Reprod Open. 2022 Mar 8;2022(2):hoac011. doi: 10.1093/hropen/hoac011. eCollection 2022.
citation: Bulow NS, Skouby SO, Warzecha AK, Udengaard H, Andersen CY, Holt MD, Grondahl ML, Nyboe Andersen A, Sopa N, Mikkelsen ALE, Pinborg A, Macklon NS. Impact of letrozole co-treatment during ovarian stimulation with gonadotrophins for IVF: a multicentre, randomized, double-blinded placebo-controlled trial. Hum Reprod. 2022 Jan 28;37(2):309-321. doi: 10.1093/humrep/deab249.