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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

Tracking Information
First Submitted Date  ICMJE August 15, 2016
First Posted Date  ICMJE October 20, 2016
Last Update Posted Date February 5, 2019
Actual Study Start Date  ICMJE August 2016
Actual Primary Completion Date January 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 20, 2018)
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
Original Primary Outcome Measures  ICMJE
 (submitted: October 19, 2016)
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, progesterone,17-hydroxyprogesterone, pregnancy associated plasma protein A and A2, Inhibin A and B, Bone morphogenic protein
Change History Complete list of historical versions of study NCT02939898 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 20, 2018)
  • 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. ]
  • 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). ]
  • Serum E2, P, Tst and Androstenedione levels [ Time Frame: The change in levels throughout the study completion, up to 3 years. ]
  • Area under the curve for P and 17-hydroxyprogesterone. [ Time Frame: The change in levels throughout the study completion, up to 3 years. ]
  • Total International Units of Follicle Stimulating Hormone used per treatment cycle. [ Time Frame: Assessed throughout study completion, up to 3 years. ]
  • Number of follicles > 12 mm [ Time Frame: Assessed throughout the study completion, up to 3 years. ]
  • Number of oocytes obtained [ Time Frame: 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. [ Time Frame: Assessed during stimulation treatment (throughout the study completion, up to 3 years). ]
  • Oocyte fertilization rate [ Time Frame: Assessed during stimulation treatment (throughout the study completion, up to 3 years). ]
  • Number and quality of embryos obtained. [ Time Frame: Assessed during stimulation treatment (throughout the study completion, up to 3 years). ]
  • Endometrial thickness [ Time Frame: Assessed throughout the study completion, up to 3 years. ]
  • Uterine contraction rate (contractions/minute) [ Time Frame: Assessed throughout the study completion, up to 3 years. ]
  • Implantation rate [ Time Frame: Assessed during stimulation treatment (throughout the study completion, up to 3 years). ]
  • 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. ]
  • 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) ]
  • 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). ]
  • 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). ]
  • Biochemical pregnancy rate [ Time Frame: Assessed during stimulation treatment (throughout the study completion, up to 3 years). ]
  • Area under the curve for E2, P and LH [ Time Frame: The change in levels throughout the study completion, up to 3 years. ]
Original Secondary Outcome Measures  ICMJE
 (submitted: October 19, 2016)
  • 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. ]
  • 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). ]
  • Serum E2, P and Tst levels [ Time Frame: The change in levels throughout the study completion, up to 3 years. ]
  • Area under the curve for P and 17-hydroxyprogesterone. [ Time Frame: The change in levels throughout the study completion, up to 3 years. ]
  • Total International Units of Follicle Stimulating Hormone used per treatment cycle. [ Time Frame: Assessed throughout study completion, up to 3 years. ]
  • Number of follicles > 12 mm [ Time Frame: Assessed throughout the study completion, up to 3 years. ]
  • Number of oocytes obtained [ Time Frame: Assessed during stimulation treatment (throughout the study completion, up to 3 years). ]
  • Proportion of oocytes resulting in top quality day 2 (or day 3) embryos according to validated morphological criteria. [ Time Frame: Assessed during stimulation treatment (throughout the study completion, up to 3 years). ]
  • Oocyte fertilization rate [ Time Frame: Assessed during stimulation treatment (throughout the study completion, up to 3 years). ]
  • Number and quality of embryos obtained. [ Time Frame: Assessed during stimulation treatment (throughout the study completion, up to 3 years). ]
  • Endometrial thickness [ Time Frame: Assessed throughout the study completion, up to 3 years. ]
  • Uterine contraction rate (contractions/minute) [ Time Frame: Assessed throughout the study completion, up to 3 years. ]
  • Implantation rate [ Time Frame: Assessed during stimulation treatment (throughout the study completion, up to 3 years). ]
  • 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. ]
  • 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) ]
  • 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). ]
  • 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). ]
  • Biochemical pregnancy rate [ Time Frame: Assessed during stimulation treatment (throughout the study completion, up to 3 years). ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Mapping the Endocrine Determinants of Ovarian Stimulation to Optimize Outcomes in Fresh Embryo Transfer Cycles
Official Title  ICMJE 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
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.

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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Infertility
Intervention  ICMJE
  • Drug: Placebo
    Adjuvant therapy to recFSH during ovarian stimulation
    Other Name: Lactose Monohydrate
  • Drug: Letrozole
    Adjuvant therapy to recFSH during ovarian stimulation
    Other Name: Aromatase Inhibitor
Study Arms  ICMJE
  • 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
    Intervention: Drug: Placebo
  • 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
    Intervention: Drug: Letrozole
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 14, 2017)
33
Original Estimated Enrollment  ICMJE
 (submitted: October 19, 2016)
32
Actual Study Completion Date  ICMJE January 2018
Actual Primary Completion Date January 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years to 40 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Denmark
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02939898
Other Study ID Numbers  ICMJE RIOTB2015
2015-005683-41 ( EudraCT Number )
H-15021852 ( Other Identifier: Ethics Committee )
HGH-2016-033_I-Suite: 04482 ( Other Identifier: Danish Data Protection Board )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: The study will share data with Study RIOT-A
Responsible Party Sven O. Skouby, Herlev Hospital
Study Sponsor  ICMJE Sven O. Skouby
Collaborators  ICMJE
  • Rigshospitalet, Denmark
  • Region Capital Denmark
  • Copenhagen University Hospital, Denmark
Investigators  ICMJE
Principal Investigator: Sven O. Skouby, Professor Unit of Reproductive Medicine, Herlev/Gentofte Hospital
PRS Account Herlev Hospital
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP