Infertility, FemalePhase 4NCT03755973
Effect of Different Ovarian Stimulation Protocols on Endometrial Receptivity
A Phase 4 study testing CFA, rFSH and Fixed daily rFSH dosing protocol of 200-300 IU in people with Infertility, Female and Endometrial Diseases, run by Instituto Valenciano de Infertilidade de Lisboa at 1 site in Portugal.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 42 years, women only
- Conditions the study is for
- Infertility, Female, Endometrial Diseases
- What is being tested?
- CFA, rFSH and Fixed daily rFSH dosing protocol of 200-300 IU
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 sitePortugal
- Study dates
- 29 Jan 2020to 22 May 2023
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 42 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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).
Show all 24Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: How do Different Ovarian Stimulation Protocols Affect Endometrial Receptivity During a Fresh In-vitro Fertilization Attempt
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.
Read the 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.
- Conditions
- Infertility, Female, Endometrial Diseases
- Being tested
- CFA, rFSH, Fixed daily rFSH dosing protocol of 200-300 IU, Step-down daily rFSH dose
- Keywords
- Endometrial receptivity, Ovarian stimulation
- Medical subject headings
- Infertility, Female, Uterine Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CFADrug
Also called Corifollitropin alpha
Long-acting exogenous ovarian stimulation
rFSHDrug
Also called Puregon, Follitropin beta
Daily rFSH
Fixed daily rFSH dosing protocol of 200-300 IUProcedure or surgery
The dose of daily rFSH is fixed at 200 or 300 IU
Step-down daily rFSH doseProcedure or surgery
The dose of daily rFSH is progressively reduced
| Study group | Role | What they receive |
|---|---|---|
| CFA plus step-down rFSH (1A) | Experimental | 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. Receives: Drug: CFA; Drug: rFSH; Procedure: Step-down daily rFSH dose |
| CFA plus fixed daily dose rFSH (1B) | Experimental | 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 Receives: Drug: CFA; Drug: rFSH; Procedure: Fixed daily rFSH dosing protocol of 200-300 IU |
| Fixed daily dose rFSH only | Active comparator | A fixed daily rFSH dosing protocol of 200 or 300 IU will be administered as ovarian stimulation Receives: Drug: rFSH; Procedure: Fixed daily rFSH dosing protocol of 200-300 IU |
What is being measured
The primary outcome is the main question the study is designed to answer.
Endometrial gene expression signature on the day of embryo transfer
RNA sequencing of specimen of endometrium
Measured: 7 days after the last day of ovarian stimulation
Secondary outcomes (1)
Serum concentrations of progesterone from the start of stimulation until the day of embryo transfer
Measurement of serum circulating progesterone levels (in ng/mL)
Measured: 3 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Nov 2018
- Study start29 Jan 2020
- Primary completion22 May 2023
- Study completion22 May 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Infertility, FemaleStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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)
- Enrolment
- 24 participants (actual)
Sponsor and investigators
- Lead sponsor
- Instituto Valenciano de Infertilidade de Lisboa
- Sponsor type
- Research network
- Collaborators
- Merck Sharp & Dohme LLC
- Responsible party
- Sponsor
- Investigators
- Samuel Santos-Ribeiro, MD PhD, Principal investigator, Instutito Valenciano de Infertilidade de Lisboa
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03755973
- Sponsor's protocol ID
- 1806-LIS-044-SD
- Status last verified
- May 2023
- First submitted
- 26 Nov 2018
- Last updated
- 1 Jun 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 1 Jun 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- How do Different Ovarian Stimulation Protocols Affect Endometrial Receptivity During a Fresh In-vitro Fertilization Attempt
- ClinicalTrials.gov ID
- NCT03755973
- Acronym / sponsor ID
- 1806-LIS-044-SD
- Conditions
- Infertility, Female, Endometrial Diseases
- Keywords
- Endometrial receptivity, Ovarian stimulation
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 24 participants (actual)
- Lead sponsor
- Instituto Valenciano de Infertilidade de LisboaResearch network
- Collaborators
- Merck Sharp & Dohme LLC
- Study start
- 29 Jan 2020 (actual)
- Primary completion
- 22 May 2023 (actual)
- Study completion
- 22 May 2023 (actual)
- First posted
- 28 Nov 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
- 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).
| Arm | Type | Receives |
|---|---|---|
| CFA plus step-down rFSH (1A) | Experimental | Drug: CFA, Drug: rFSH, Procedure: Step-down daily rFSH doseA 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. |
| CFA plus fixed daily dose rFSH (1B) | Experimental | Drug: CFA, Drug: rFSH, Procedure: Fixed daily rFSH dosing protocol of 200-300 IUA 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 |
| Fixed daily dose rFSH only | Active comparator | Drug: rFSH, Procedure: Fixed daily rFSH dosing protocol of 200-300 IUA fixed daily rFSH dosing protocol of 200 or 300 IU will be administered as ovarian stimulation |
Who may qualify
- Ages
- 18 to 42 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (9 listed)
- 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.
Key exclusion criteria (24 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CFAAlso: Corifollitropin alphaLong-acting exogenous ovarian stimulation | Drug | CFA plus fixed daily dose rFSH (1B), CFA plus step-down rFSH (1A) |
| rFSHAlso: Puregon, Follitropin betaDaily rFSH | Drug | CFA plus fixed daily dose rFSH (1B), CFA plus step-down rFSH (1A), Fixed daily dose rFSH only |
| Fixed daily rFSH dosing protocol of 200-300 IUThe dose of daily rFSH is fixed at 200 or 300 IU | Procedure or surgery | CFA plus fixed daily dose rFSH (1B), Fixed daily dose rFSH only |
| Step-down daily rFSH doseThe dose of daily rFSH is progressively reduced | Procedure or surgery | CFA plus step-down rFSH (1A) |
Primary outcome
Endometrial gene expression signature on the day of embryo transfer
Time frame: 7 days after the last day of ovarian stimulation
RNA sequencing of specimen of endometrium
1 secondary outcome
Serum concentrations of progesterone from the start of stimulation until the day of embryo transfer
Time frame: 3 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Jun 2023.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Samuel Santos-Ribeiro, MD PhD principal investigator
Instutito Valenciano de Infertilidade de Lisboa
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing CFA, rFSH and Fixed daily rFSH dosing protocol of 200-300 IU in people with Infertility, Female and Endometrial Diseases, run by Instituto Valenciano de Infertilidade de Lisboa at 1 site in Portugal.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Jun 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Portugal. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Endometrial gene expression signature on the day of embryo transfer (time frame: 7 days after the last day of ovarian stimulation). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Jun 2023.