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Effect of Different Ovarian Stimulation Protocols on Endometrial Receptivity

Primary Purpose

Infertility, Female, Endometrial Diseases

Status
Completed
Phase
Phase 4
Locations
Portugal
Study Type
Interventional
Intervention
CFA
rFSH
Fixed daily rFSH dosing protocol of 200-300 IU
Step-down daily rFSH dose
Sponsored by
Instituto Valenciano de Infertilidade de Lisboa
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Infertility, Female focused on measuring Endometrial receptivity, Ovarian stimulation

Eligibility Criteria

18 Years - 42 Years (Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

  1. Informed consent form (ICF) dated and signed.
  2. Age: ≥18 and <40 years old.
  3. AFC ≥5 and <20.
  4. AMH ≥1.1 ng/mL and <2.5 ng/mL, performed in the 12 months prior to inclusion.
  5. Body Mass Index (BMI): ≥18.5 Kg/m2 and <30 Kg/m2.
  6. Weight: ≥50 kg and <80 kg.
  7. First or second ART cycle or fertility preservation cycle.
  8. Regular menstrual cycles (between 22 and 35 days).
  9. Two ovaries present.
  10. Pregnancy-wish.
  11. Planned for single blastocyst transfer.

Exclusion Criteria:

  1. Simultaneous participation in another clinical study.
  2. Previous history of poor ovarian response (<4 oocytes retrieved) with a maximal dose of OS (≥300 IU/day) or OHSS, regardless of gonadotropin dose.
  3. Known reasons for impaired implantation (i.e. hydrosalpinx, fibroid distorting the endometrial cavity, Asherman's syndrome, thrombophilia or endometrial tuberculosis).
  4. Repeated miscarriages (>2 previous biochemical pregnancies or >2 spontaneous miscarriages).
  5. Recurrent implantation failure (>3 failed cycles with good quality embryos).
  6. Polycystic ovary syndrome (PCOS).
  7. Tumours of the ovary, breast, uterus, pituitary or hypothalamus.
  8. Abnormal (not menstrual) vaginal bleeding without a known/diagnosed cause.
  9. Ovarian cysts or enlarged ovaries.
  10. Fibroid tumours of the uterus incompatible with pregnancy.
  11. Malformations of the reproductive organs incompatible with pregnancy.
  12. Primary gonadal failure.
  13. Renal impairment defined as estimated glomerular filtration rate of 90 ml/min/1.73 m2 determined by the Modified Diet and Renal Disease (MDRD) equation at screening.
  14. Previous antibiotic hypersensitivity reactions (streptomycin and/or neomycin).
  15. Risk factors for thromboembolic events, such as a personal or family history, severe obesity or thrombophilia.
  16. Moderate or severe hepatic impairment.
  17. Untreated and uncontrolled thyroid dysfunction.
  18. Current use of oral contraceptive, anti-depressants, anti-psychotics, steroids, anti-epileptics or chemotherapy.
  19. Administration of exogenous Estradiol (E2), Progesterone (P4) or gonadotropins in the preceding menstrual cycle.
  20. Active female smoking.
  21. Acceptors of donated oocytes/embryos.
  22. Ongoing pregnancy.
  23. Women who have previously enrolled in the trial.
  24. Those unable to comprehend the investigational nature of the proposed study.

Sites / Locations

  • Instituto Valenciano de Infertilidade

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Active Comparator

Arm Label

CFA plus step-down rFSH (1A)

CFA plus fixed daily dose rFSH (1B)

Fixed daily dose rFSH only

Arm Description

A single dose of 150 IU of CFA followed by daily rFSH will be administered. The initial rFSH administration will be dosed between 100 IU and 200 IU according to the following criteria: 200 or 300 IU: <3 follicles above 13 mm visible on transvaginal ultrasound; 150 IU, >2 follicles above 13 mm and circulating day-8 follicle-stimulating hormone (FSH) levels ≤20 IU/mL. 100 IU, >2 follicles above 13 mm and circulating day-8 FSH levels >20 IU/mL; Subjects will perform a step-down daily rFSH dose (fixed decreases in the dosing of 25 IU/day) until the triggering criteria are met or a minimum of 50 IU/day is reached. Subjects with <3 follicles above 13 mm visible will maintain 200 IU/day of rFSH until this criterion is met, initiating a fixed 25 IU/day stepdown protocol only from then onwards.

A single dose of 150 IU of CFA followed by a fixed daily rFSH dosing protocol of 200 or 300 IU will be administered as ovarian stimulation

A fixed daily rFSH dosing protocol of 200 or 300 IU will be administered as ovarian stimulation

Outcomes

Primary Outcome Measures

Endometrial gene expression signature on the day of embryo transfer
RNA sequencing of specimen of endometrium

Secondary Outcome Measures

Serum concentrations of progesterone from the start of stimulation until the day of embryo transfer
Measurement of serum circulating progesterone levels (in ng/mL)

Full Information

First Posted
November 26, 2018
Last Updated
May 31, 2023
Sponsor
Instituto Valenciano de Infertilidade de Lisboa
Collaborators
Merck Sharp & Dohme LLC
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1. Study Identification

Unique Protocol Identification Number
NCT03755973
Brief Title
Effect of Different Ovarian Stimulation Protocols on Endometrial Receptivity
Official Title
How do Different Ovarian Stimulation Protocols Affect Endometrial Receptivity During a Fresh In-vitro Fertilization Attempt
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Completed
Study Start Date
January 29, 2020 (Actual)
Primary Completion Date
May 22, 2023 (Actual)
Study Completion Date
May 22, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Instituto Valenciano de Infertilidade de Lisboa
Collaborators
Merck Sharp & Dohme LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This study will assess the change in endometrial gene expression signature on the day of embryo transfer according to the type of exogenous gonadotropins administered.
Detailed Description
Late-follicular elevated progesterone (LFEP) following ovarian stimulation for assisted reproductive technologies (ART) has been linked to abnormal endometrial receptivity expression profiles and lower pregnancy rates. For this reason, physicians frequently propose that patients with LFEP avoid performing a fresh embryo transfer, postponing instead it to a subsequent unstimulated cycle. Although this strategy may reduce the detrimental effect LFEP may have on cumulative ART pregnancy rates, it may also frustrate couples who wish to become pregnant as soon as possible. With the intent of minimizing potentially-avoidable treatment delays, an increasing number of researchers are proposing that physicians revisit their current ovarian stimulation regimens. One strategy which may reduce the incidence of LFEP is to decrease the dose of gonadotropins administered at the end of stimulation (i.e. a stepdown protocol). A similar approach, using corifollitropin alpha (CFA), has also been recently advanced, taking advantage of the stepdown-like pharmacodynamic profile of this compound. In order to assess the clinical usefulness of these strategies, the investigators propose a single-center, open-label, paired, randomized trial. The main objective of this study is to assess the changes in the endometrial gene expression profile on the day of fresh embryo transfer according to the type of gonadotropins administered for ovarian stimulation. In summary, all consenting subjects will first undergo an endometrial biopsy seven days after the luteinizing hormone peak in an unmedicated natural cycle. This biopsy will serve as the baseline endometrial biopsy (natural cycle biopsy) for a gene expression analysis. Following this baseline biopsy, subjects will be randomly allocated to a specific type of ovarian stimulation regimen in order to later perform a second endometrial biopsy, this time five days after oocyte retrieval (stimulated cycle biopsy). Subjects will be randomized to administer, on the third day of their menstrual cycle, either a single dose of 150 IU of CFA (study arms 1A and 1B) or a fixed daily dose of 200 or 300 IU of recombinant follicle stimulating (rFSH, study arm 2). On the eighth day of stimulation, it is expected that 15% to 30% of all subjects who performed CFA will have reached the follicular development criteria for final oocyte maturation and ovulation triggering.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Infertility, Female, Endometrial Diseases
Keywords
Endometrial receptivity, Ovarian stimulation

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
All consenting subjects will first undergo an endometrial biopsy seven days after the luteinizing hormone (LH) peak in an unmedicated natural cycle. This biopsy will serve as the baseline endometrial biopsy (natural cycle biopsy) for the gene expression signature analysis. Following this baseline biopsy, the subjects will be randomly allocated to a specific type of ovarian stimulation regimen in order to later perform some second endometrial biopsy, five days after oocyte retrieval (stimulated cycle biopsy).
Masking
None (Open Label)
Allocation
Randomized
Enrollment
24 (Actual)

8. Arms, Groups, and Interventions

Arm Title
CFA plus step-down rFSH (1A)
Arm Type
Experimental
Arm Description
A single dose of 150 IU of CFA followed by daily rFSH will be administered. The initial rFSH administration will be dosed between 100 IU and 200 IU according to the following criteria: 200 or 300 IU: <3 follicles above 13 mm visible on transvaginal ultrasound; 150 IU, >2 follicles above 13 mm and circulating day-8 follicle-stimulating hormone (FSH) levels ≤20 IU/mL. 100 IU, >2 follicles above 13 mm and circulating day-8 FSH levels >20 IU/mL; Subjects will perform a step-down daily rFSH dose (fixed decreases in the dosing of 25 IU/day) until the triggering criteria are met or a minimum of 50 IU/day is reached. Subjects with <3 follicles above 13 mm visible will maintain 200 IU/day of rFSH until this criterion is met, initiating a fixed 25 IU/day stepdown protocol only from then onwards.
Arm Title
CFA plus fixed daily dose rFSH (1B)
Arm Type
Experimental
Arm Description
A single dose of 150 IU of CFA followed by a fixed daily rFSH dosing protocol of 200 or 300 IU will be administered as ovarian stimulation
Arm Title
Fixed daily dose rFSH only
Arm Type
Active Comparator
Arm Description
A fixed daily rFSH dosing protocol of 200 or 300 IU will be administered as ovarian stimulation
Intervention Type
Drug
Intervention Name(s)
CFA
Other Intervention Name(s)
Corifollitropin alpha
Intervention Description
Long-acting exogenous ovarian stimulation
Intervention Type
Drug
Intervention Name(s)
rFSH
Other Intervention Name(s)
Puregon, Follitropin beta
Intervention Description
Daily rFSH
Intervention Type
Procedure
Intervention Name(s)
Fixed daily rFSH dosing protocol of 200-300 IU
Intervention Description
The dose of daily rFSH is fixed at 200 or 300 IU
Intervention Type
Procedure
Intervention Name(s)
Step-down daily rFSH dose
Intervention Description
The dose of daily rFSH is progressively reduced
Primary Outcome Measure Information:
Title
Endometrial gene expression signature on the day of embryo transfer
Description
RNA sequencing of specimen of endometrium
Time Frame
7 days after the last day of ovarian stimulation
Secondary Outcome Measure Information:
Title
Serum concentrations of progesterone from the start of stimulation until the day of embryo transfer
Description
Measurement of serum circulating progesterone levels (in ng/mL)
Time Frame
3 weeks

10. Eligibility

Sex
Female
Gender Based
Yes
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
42 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Informed consent form (ICF) dated and signed. Age: ≥18 and ≤42 years old. AFC <20. AMH <2.5 ng/mL, performed in the 12 months prior to inclusion. Body Mass Index (BMI): ≥18.5 Kg/m2 and <30 Kg/m2. Weight: ≥50 kg and <80 kg. First or second ART cycle (with pregnancy wish and planned for single blastocyst transfer) at the study site, or fertility preservation cycle. Regular menstrual cycles (between 22 and 35 days). Two ovaries present. Exclusion Criteria: Simultaneous participation in another clinical study. Previous history of poor ovarian response (<4 oocytes retrieved) with a maximal dose of OS (≥300 IU/day) or OHSS, regardless of gonadotropin dose. Known reasons for impaired implantation (i.e. hydrosalpinx, fibroid distorting the endometrial cavity, Asherman's syndrome, thrombophilia or endometrial tuberculosis). Repeated miscarriages (>2 previous biochemical pregnancies or >2 spontaneous miscarriages). Recurrent implantation failure (>3 failed cycles with good quality embryos). Polycystic ovary syndrome (PCOS). Tumours of the ovary, breast, uterus, pituitary or hypothalamus. Abnormal (not menstrual) vaginal bleeding without a known/diagnosed cause. Ovarian cysts or enlarged ovaries. Fibroid tumours of the uterus incompatible with pregnancy. Malformations of the reproductive organs incompatible with pregnancy. Primary gonadal failure. Renal impairment defined as estimated glomerular filtration rate of 90 ml/min/1.73 m2 determined by the Modified Diet and Renal Disease (MDRD) equation at screening. Previous antibiotic hypersensitivity reactions (streptomycin and/or neomycin). Risk factors for thromboembolic events, such as a personal or family history, severe obesity or thrombophilia. Moderate or severe hepatic impairment. Untreated and uncontrolled thyroid dysfunction. Current use of oral contraceptive, anti-depressants, anti-psychotics, steroids, anti-epileptics or chemotherapy. Administration of exogenous Estradiol (E2), Progesterone (P4) or gonadotropins in the preceding menstrual cycle. Active female smoking. Acceptors of donated oocytes/embryos. Ongoing pregnancy. Women who have previously enrolled in the trial. Those unable to comprehend the investigational nature of the proposed study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Samuel Santos-Ribeiro, MD PhD
Organizational Affiliation
Instutito Valenciano de Infertilidade de Lisboa
Official's Role
Principal Investigator
Facility Information:
Facility Name
Instituto Valenciano de Infertilidade
City
Lisboa
Country
Portugal

12. IPD Sharing Statement

Plan to Share IPD
No

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Effect of Different Ovarian Stimulation Protocols on Endometrial Receptivity

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