RIOTC: Reducing the Impact of Ovarian Stimulation. Novel Approaches to Luteal Support in IVF-Study 2 (RIOTC)

RIOTC: Reducing the Impact of Ovarian Stimulation. Novel Approaches to Luteal Support in IVF - Study 2

The goal of the randomised controlled study (RCT) is to identify novel strategies that can improve the luteal phase endocrinology after ovarian stimulation, with the aim of using less or no luteal support in IVF while making the endometrium thinner and more receptive to embryo implantation.

Study Overview

• Status: Completed
• Conditions: IVF
• Intervention / Treatment: Drug: Letrozole 5 mg

Detailed Description

The high estradiol levels generated in IVF by multiple dominant follicles at the follicular-luteal phase transition generate powerful negative feedback at the pituitary gland, effectively switching off gonadotropin production. Without stimulation by endogenous luteinizing hormone (LH), the corpora lutea undergo involution and menstruation follows, preventing the establishment of pregnancy.

To address these detrimental effects of ovarian stimulation, the investigators will do a RCT with the use of aromatase inhibitors, which suppress the conversion of androgens to estrogens to ameliorate the unwanted effects of high estrogens.

This study is designed to test the hypothesis that preventing supra-physiological estrogen levels during ovarian stimulation restricts pituitary suppression sufficiently to allow LH levels to rise and support the corpora lutea, leading to a normal post-ovulatory luteal phase, evidenced by a normal duration and luteal phase endocrine profile. To test this, consenting oocyte donors will be randomized to receive co-treatment with aromatase inhibitors or no co-treatment during ovarian stimulation. Following oocyte retrieval, no luteal support will be provided to donors in both Groups.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Herlev, Denmark, 2730
    • Herlev Hospitals Fertilitetsklinik
  • Køge, Denmark, 4600
    • Sjællands Fertilitetsklinik

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Meet the clinical criteria for acceptance as oocyte donors (healthy women who volunteers to donate oocytes to other women).
• Regular ovulatory cycle of 26-32 days.
• Age: 18-35 years old.
• Written consent.

Exclusion Criteria:

• Contraindications for ovarian stimulation or aspiration of oocytes according to local guidelines
• Polycystic Ovary Syndrome (PCOS)
• Allergy towards study drug
• Women who have had a hormone or copper intra-uterine device (IUD) within 3 months

Exclusion of patients after earlier inclusion in the study in case of

• Patient withdrawal of consent
• Lack of compliance with medication
• Medical complication arising from IVF treatment that requires the cycle to be terminated
• Serious adverse events (SAE) or serious adverse reactions (SAR) including severe allergy to study drug.
• Specific ARs to study drug: severe degree of hot flushed, severe degree of nausea/vomiting, severe diarrhea, severe degree of muscle and joint pain.

In case of exclusion of a patient after earlier inclusion in the study, a new patient will be included.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention; recFSH and co-treatment with letrozole 5 mg/day from stimulation day 1 on cycle day 2 or 3 until the day before gonadotrophin releasing hormone(GnRH) agonist administration to trigger final oocyte maturation. GnRH antagonist 0.25 mg/day from stimulation day 5 until day of GnRH agonist administration. No luteal phase support.	Drug: Letrozole 5 mg; recFSH and co-treatment with letrozole 5 mg/day from stimulation day 1 on cycle day 2 or 3 until the day before GnRH agonist administration to trigger final oocyte maturation. GnRH antagonist 0.25 mg/day from stimulation day 5 until day of GnRH agonist administration. No luteal phase support.; Other Names: Aromatase inhibitor
No Intervention: Control group; recFSH from stimulation day 1 on cycle day 2 or 3 until the day before GnRH agonist administration to trigger final oocyte maturation. GnRH antagonist 0.25 mg/day from stimulation day 5 until day of GnRH agonist administration. No luteal phase support.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of luteal phase (days from aspiration untill bleeding)	Difference in lengths of days until bleeding (from aspiration until first day of bleeding) of the luteal phase between intervention group and control group.	Up to three weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase of endometrial receptivity according to Endometrial Receptivity Array (ERA) test	Difference in established endometrial tissue and secretion markers of endometrial receptivity between intervention group and controls (genomic profile assessed by ERA test).	ERA-test is taken 5 days after aspiration of oocytes.
Estradiol (E2),progesterone (P), luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels.	Differences in the area under the curve for plasma E2, P, LH and FSH levels from day of OPU until day 14 post OPU between intervention group and control group.	Blood samples are taken on 1 day of oocyte aspiration, 2 days after, 5 days after and 14 days after.
Endometrium thickness.	Difference in endometrium thickness 5 days post oocyte pick-up (OPU) between intervention group and controls.	Endometrium thickness is measured on 1 day of oocyte aspiration, 2 days after and 5 days after.

Collaborators and Investigators

• Sponsor: Nicholas Macklon
• Collaborators: Gedeon Richter Ltd.; Igenomix
• Investigators: Principal Investigator: Nicholas Stephen Macklon, Professor, Professor; Study Director: Marianne Dreyer Holt, MD, PhD student

Publications and helpful links

General Publications

• Dreyer Holt M, Skouby SO, Bulow NS, Englund ALM, Birch Petersen K, Macklon NS. The Impact of Suppressing Estradiol During Ovarian Stimulation on the Unsupported Luteal Phase: A Randomized Controlled Trial. J Clin Endocrinol Metab. 2022 Aug 18;107(9):e3633-e3643. doi: 10.1210/clinem/dgac409.

Study record dates

Study Major Dates

• Study Start (Actual): September 18, 2018
• Primary Completion (Actual): November 30, 2020
• Study Completion (Actual): November 30, 2020

Study Registration Dates

• First Submitted: September 7, 2018
• First Submitted That Met QC Criteria: August 21, 2020
• First Posted (Actual): August 24, 2020

Study Record Updates

• Last Update Posted (Actual): January 14, 2021
• Last Update Submitted That Met QC Criteria: January 13, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Letrozole, aromatase inhibitor, luteal phase, IVF
• Additional Relevant MeSH Terms: 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: REG-210-2017; 2017-004433-93 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No