Effect of Addition of Aromatase Inhibitor to Ovarian Stimulation Therapy in IVF Treatment (RIOT-A)

Reducing the Impact of Ovarian Stimulation - The RIOT Project. Study RIOT-A: The Role of Aromatase Inhibitor in Reducing the Detrimental Effects of Ovarian Stimulation to Optimize Outcomes in Fresh Embryo Transfer Cycles

Rigshospitalet, Denmark, Hvidovre University Hospital, Holbaek Sygehus, Region Capital Denmark, Copenhagen University Hospital, Denmark, Zealand University Hospital

This project seeks to determine whether estradiol suppression achieved with adjuvant treatment with an aromatase inhibitor improves end-follicular and midluteal phase parameters during IVF. 128 patients will be randomized to either placebo or active treatment.

The aim of the study is to investigate whether the detrimental effects of ovarian stimulation on outcomes in fresh embryo transfer cycles be ameliorated by co-treatment with aromatase inhibitors? The research questions are: Can the impact of ovarian stimulation on late follicular phase sex steroid levels (and hence endometrial receptivity) be mitigated by co-treatment with aromatase inhibitors during ovarian stimulation? Does co-treatment with aromatase inhibitors 'normalize' the endocrinology of the midluteal phase

2 tablets of placebo are administered daily from stimulation start to day before hCG as adjunctive therapy to 150 IU of recFSH

2 tablets of 2,5mg Letrozole are administered daily from stimulation start to day before hCG as adjunctive therapy to 150 IU of recFSH

Assessed during stimulation treatment on day before hCG injection (throughout the study completion, up to 3 years)

Assessed on stimulation day 5, day of hCG administration (or the day before), day 7 and 10 after hCG administration. Assessed throughout study completion, up to 3 years.

Assessed in stimulated cycle on day of hCG administration or the day before (throughout the study completion), up to 3 years. Cycle length is between 21 and 35 days

Assessed in stimulated cycle at time of oocyte pick up after follicle aspiration (throughout the study completion, up to 3 years).Cycle length is between 21 and 35 days

Proportion of oocytes resulting in top quality day 2, day 3 embryos or day 5/6 embryos according to validated morphological criteria.

Assessed at day 2-3 after oocyte pick up following stimulation (throughout study completion, up to 3 years)

Assessed 2 weeks after embryo transfer following stimulation (throughout study completion, up to 3 years)

Pregnancy scan at gestational age week 7-8 (3-4 weeks after the positive hCG in serum). Assessed throughout study completion, up to 3 years.

Morphokinetic parameters of embryo quality as measured using a Time Lapse analysis in centers employing this technology.

Assessed from time of oocyte pick-up to embryo transfer following stimulation (throughout study completion, up to 3 years)

From start of stimulation and administration of study medication to pregnancy scan week gestational age 7-8. Assessed throughout study completion, up to 3 years.

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 AMH 8- 32 (both included) Written consent 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

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.