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

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ClinicalTrials.gov Identifier: NCT02939898
Recruitment Status : Completed
First Posted : October 20, 2016
Last Update Posted : February 5, 2019
Sponsor:
Collaborators:
Rigshospitalet, Denmark
Region Capital Denmark
Copenhagen University Hospital, Denmark
Information provided by (Responsible Party):
Sven O. Skouby, Herlev Hospital

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.


Condition or disease Intervention/treatment Phase
Infertility Drug: Placebo Drug: Letrozole Phase 2 Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 33 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : August 2016
Actual Primary Completion Date : January 2018
Actual Study Completion Date : January 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Letrozole

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 Name: 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 Name: Aromatase Inhibitor




Primary Outcome Measures :
  1. Size of follicle cohort in relation to serum endocrine and paracrine markers [ Time Frame: 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. ]
    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


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


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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02939898


Locations
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Denmark
Unit of Reproductive Medicine, Herlev Hospital
Herlev, Capital Region, Denmark, 2730
Sponsors and Collaborators
Sven O. Skouby
Rigshospitalet, Denmark
Region Capital Denmark
Copenhagen University Hospital, Denmark
Investigators
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Principal Investigator: Sven O. Skouby, Professor Unit of Reproductive Medicine, Herlev/Gentofte Hospital

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Responsible Party: Sven O. Skouby, Professor, Herlev Hospital
ClinicalTrials.gov Identifier: NCT02939898     History of Changes
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 )
First Posted: October 20, 2016    Key Record Dates
Last Update Posted: February 5, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The study will share data with Study RIOT-A
Additional relevant MeSH terms:
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Infertility
Genital Diseases, Male
Genital Diseases, Female
Letrozole
Aromatase Inhibitors
Antineoplastic Agents
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs