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

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.

Study Overview

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

Detailed Description

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:

1. 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?
2. Does co-treatment with aromatase inhibitors 'normalize' the endocrinology of the midluteal phase

• Study Type: Interventional
• Enrollment (Actual): 129
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Capital Region
    • Herlev, Capital Region, Denmark, 2730
      • Unit of Reproductive Medicine, Herlev Hospital
  • Capitol Region
    • Copenhagen, Capitol Region, Denmark, 2100
      • Department of Fertility, Juliane Marie Centeret
    • Hvidovre, Capitol Region, Denmark, 2650
      • Clinic of Fertility, Hvidovre Hospital
  • Region Of Zealand
    • Holbæk, Region Of Zealand, Denmark, 4300
      • Clinic of Fertility, Holbæk 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
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• 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 IU of recFSH	Drug: Placebo; Adjuvant therapy to recFSH during ovarian stimulation; Other Names: Lactose Monohydrate
Active Comparator: Letrozole 5mg; 2 tablets of 2,5mg Letrozole are administered daily from stimulation start to day before hCG as adjunctive therapy to 150 IU 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	Time Frame
Serum progesterone level	Assessed during stimulation treatment on day before hCG injection (throughout the study completion, up to 3 years)

Secondary Outcome Measures

Outcome Measure	Time Frame
Serum estradiol, testosterone and androstenedione levels	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.
P and 17-hydroxyprogesterone (17-HP) Area Under the Curve.	Assessed during stimulation treatment throughout the study completion, up to 3 years.
Follicular fluid concentration of estradiol, testosterone, inhibin B and AMH levels	Assessed during stimulation treatment (throughout the study completion, up to 3 years
Total IU of Follicle Stimulating Hormone used per cycle.	Assessed throughout study completion, up to 3 years
Number of follicles > 12 mm	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
Number of oocytes obtained oocytes obtained.	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)
Oocyte fertilization rate	Assessed during stimulation treatment (throughout the study completion, up to 3 years
Number and quality of embryos obtained, including rate of blastocyst formation.	Assessed during stimulation treatment (throughout the study completion, up to 3 years
Endometrial thickness in millimeters	Assessed throughout the study completion, up to 3 years
Implantation rate	Assessed during stimulation treatment (throughout the study completion, up to 3 years
Biochemical pregnancy rate	Assessed 2 weeks after 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 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)
Reported side effects	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.

Collaborators and Investigators

• Sponsor: Sven O. Skouby
• Collaborators: Zealand University Hospital; Rigshospitalet, Denmark; Hvidovre University Hospital; Region Capital Denmark; Holbaek Sygehus; 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2017
• Primary Completion (Actual): October 30, 2018
• Study Completion (Actual): October 30, 2018

Study Registration Dates

• First Submitted: July 11, 2016
• First Submitted That Met QC Criteria: October 25, 2016
• First Posted (Estimate): October 27, 2016

Study Record Updates

• Last Update Posted (Actual): July 8, 2019
• Last Update Submitted That Met QC Criteria: July 4, 2019
• Last Verified: July 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: RIOTA2015; 2015-005682-24 (EudraCT Number); H-15021850 (Other Identifier: Ethics Committee); HGH-2016-045_04513 (Other Identifier: Danish Data Protection Board)

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