Mapping the Endocrine Determinants of Ovarian Stimulation to Optimize Outcomes in Fresh Embryo Transfer Cycles (RIOT-B)

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

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.

Study Overview

• Status: Completed
• Conditions: Infertility
• Intervention / Treatment: Drug: Placebo; Drug: Letrozole

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.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Capital Region
    • Herlev, Capital Region, Denmark, 2730
      • Unit of Reproductive Medicine, Herlev Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Lactose Monohydrate; 2 tablets of placebo are administered daily from stimulation start to day before hCG as adjunctive therapy to 150 International Units of recFSH	Drug: Placebo; Adjuvant therapy to recFSH during ovarian stimulation; Other Names: Lactose Monohydrate
Active Comparator: Letrozole; 2 tablets of 2,5 mg Letrozole are administered daily from stimulation start to day before hCG as adjunctive therapy to 150 International Units of recFSH	Drug: Letrozole; Adjuvant therapy to recFSH during ovarian stimulation; Other Names: Aromatase Inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Size of follicle cohort in relation to serum endocrine and paracrine markers	Markers for analysis include: anti-muellerian hormone, estradiol, follicle stimulating hormone, luteinizing hormone, testosterone, androstenedione, progesterone,17-hydroxyprogesterone, pregnancy associated plasma protein A and A2, Inhibin A and B, Bone morphogenic protein	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 Outcome Measures

Outcome Measure	Time Frame
Size of the cyclically recruited follicle cohort after ovarian stimulation with and without co-treatment with Aromatase Inhibitor.	The change in size of follicle cohort throughout the study completion, up to 3 years.
Expression of cytokine and growth factors in endometrial secretions following co-treatment with Aromatase Inhibitor compared with placebo control.	Assessed in stimulated cycle at time of embryo transfer (throughout study completion, up to 3 years).
Serum E2, P, Tst and Androstenedione levels	The change in levels throughout the study completion, up to 3 years.
Area under the curve for P and 17-hydroxyprogesterone.	The change in levels throughout the study completion, up to 3 years.
Total International Units of Follicle Stimulating Hormone used per treatment cycle.	Assessed throughout study completion, up to 3 years.
Number of follicles > 12 mm	Assessed throughout the study completion, up to 3 years.
Number of oocytes obtained	Assessed during stimulation treatment (throughout the study completion, up to 3 years).
Proportion of oocytes resulting in top quality day 2, day 3 embryos or day 5/6 embryos according to validated morphological criteria.	Assessed during stimulation treatment (throughout the study completion, up to 3 years).
Oocyte fertilization rate	Assessed during stimulation treatment (throughout the study completion, up to 3 years).
Number and quality of embryos obtained.	Assessed during stimulation treatment (throughout the study completion, up to 3 years).
Endometrial thickness	Assessed throughout the study completion, up to 3 years.
Uterine contraction rate (contractions/minute)	Assessed throughout the study completion, up to 3 years.
Implantation rate	Assessed during stimulation treatment (throughout the study completion, up to 3 years).
Reported side effects	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.
Morphokinetic parameters of embryo quality as measured using a Time Lapse analysis.	Assessed from time of oocyte pick-up to embryo transfer following stimulation (throughout study completion, up to 3 years)
Clinical pregnancy rate	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).
Follicular fluid endocrine and paracrine markers following co-treatment with Aromatase Inhibitor compared with placebo control.	Assessed during stimulation treatment (throughout the study completion, up to 3 years).
Biochemical pregnancy rate	Assessed during stimulation treatment (throughout the study completion, up to 3 years).
Area under the curve for E2, P and LH	The change in levels throughout the study completion, up to 3 years.

Collaborators and Investigators

• Sponsor: Sven O. Skouby
• Collaborators: Rigshospitalet, Denmark; Region Capital Denmark; Copenhagen University Hospital, Denmark

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2016
• Primary Completion (Actual): January 1, 2018
• Study Completion (Actual): January 1, 2018

Study Registration Dates

• First Submitted: August 15, 2016
• First Submitted That Met QC Criteria: October 19, 2016
• First Posted (Estimate): October 20, 2016

Study Record Updates

• Last Update Posted (Actual): February 5, 2019
• Last Update Submitted That Met QC Criteria: February 4, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infertility; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Steroid Synthesis Inhibitors; Estrogen Antagonists; Letrozole; Aromatase Inhibitors
• Other Study ID Numbers: RIOTB2015; 2015-005683-41 (EudraCT Number); H-15021852 (Other Identifier: Ethics Committee); HGH-2016-033_I-Suite: 04482 (Other Identifier: Danish Data Protection Board)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The study will share data with Study RIOT-A