MiscarriagePhase 4NCT03976544
Natural Cycle Versus Hormone Replacement Therapy Cycle for a Frozen-thawed Embryo Transfer in PGT Patients
A Phase 4 study testing Estradiol Valerate and Micronized progesterone in people with Miscarriage and Frozen Embryo Transfer, run by CRG UZ Brussel at 1 site in Belgium.
Trial summary
The aim of the current study is to compare miscarriage rates (before 8 weeks) between a true natural cycle (awaiting spontaneous LH surge) and a hormone replacement therapy cycle prior to blastocyst transfer in preimplantation genetic testing (PGT) patients, with biopsy on day 5 of embryonic development. Read more about this study
- Who is it for?
- Ages 18 to 42 years, women only
- Conditions the study is for
- Miscarriage, Frozen Embryo Transfer, Natural Cycle
- What is being tested?
- Estradiol Valerate and Micronized progesterone
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 362 participants
- Where
- 1 siteBelgium
- Study dates
- 25 May 2019to 1 Jan 2025
- 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
- BMI under 35 kg/m2
- Regular menstrual cycle pattern (i.e. 24-35 days cycle)
- First, second and third ICSI-PGT cycle
- First frozen embryo transfer cycle following a fresh ICSI-PGT attempt
- PGT with trophectoderm biopsy on day 5 of embryonic development
- Signed informed consent
Who cannot join
- Oligo-amenorrhea
- BMI above 35
- Contraindications for the use of hormonal replacement therapy
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Natural Cycle Versus Hormone Replacement Therapy Cycle for a Frozen-thawed Embryo Transfer in PGT Patients: A Randomized Trial
The aim of the current study is to compare miscarriage rates (before 8 weeks) between a true natural cycle (awaiting spontaneous LH surge) and a hormone replacement therapy cycle prior to blastocyst transfer in preimplantation genetic testing (PGT) patients, with biopsy on day 5 of embryonic development. The advantage of performing the study in PGT patients is the exclusion of aneuploidy as a cause of miscarriage.
- Conditions
- Miscarriage, Frozen Embryo Transfer, Natural Cycle, Hormone Replacement Therapy Cycle, Preimplantation Genetic Screening, Euploid Embryos
- Being tested
- Estradiol Valerate, Micronized progesterone
- Keywords
- frozen-thawed embryo transfer, FET, natural cycle, hormone replacement therapy cycle, miscarriage
- Medical subject headings
- Abortion, Spontaneous
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Estradiol ValerateDrug
Also called Progynova
Estradiol valerate will be started in the beginning of the menstrual cycle in order to induce proliferation of the endometrium.
Micronized progesteroneDrug
Also called Utrogestan
If the endometrium is considered adequately proliferated, micronized progesterone is administered and frozen-thawed blastocyst transfer will take place on the 6th day of supplementation.
| Study group | Role | What they receive |
|---|---|---|
| Natural cycle | No intervention | Patients are asked to perform a blood sample, with evaluation of serum estradiol (E2), progesterone (P), luteinizing hormone (LH) and follicle stimulating hormone (FSH), on the first or second day of the menstrual cycle. If these serum hormonal values are considered basal for the beginning of the follicular phase, patients are asked to come back on day 10 to 12 of the cycle for blood sample and transvaginal ultrasound scan in order to assess follicular growth. The timing of ovulation is determined based on a combination of ultrasonography features (the presence of a dominant follicle and adequate endometrium) and endocrine hormonal values in serum blood samples. Ovulation is generally defined as an, at least, 180% increase of LH compared to the mean level in the previous 24h. Frozen-warmed blastocyst transfer will take place six days following the spontaneous LH surge. |
| Hormone replacement therapy cycle | Experimental | Patients are asked to perform a blood sample, with evaluation of serum estradiol (E2), progesterone (P), luteinizing hormone (LH) and follicle stimulating hormone (FSH) on the first or second day of the menstrual cycle. If these values are considered basal for the beginning of the follicular phase, estrogen supplementation (Estradiol valerate, Progynova® 3x2mg/day) is started to induce proliferation of the endometrium. Blood sample and transvaginal ultrasound are thereafter performed ten to fourteen days later. If the endometrium is considered adequate (generally considered if triple line and above 6,5 mm thickness), embryo transfer is scheduled on the sixth day of progesterone (vaginal micronized progesterone, Utrogestan® 2x200mg twice a day) supplementation.
In case of escape spontaneous ovulation embryo transfer will be performed considering the presumable time of ovulation. Receives: Drug: Estradiol Valerate; Drug: Micronized progesterone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Miscarriage rate before 8 weeks of gestation
a spontaneous loss of a clinical pregnancy before 8 weeks of gestational age, in which the embryo(s) is/are nonviable and is/are (not) spontaneously absorbed or expelled from the uterus per initiated embryo transfer cycle and per positive hCG
Measured: 8 weeks
Secondary outcomes (3)
Miscarriage rate after 8 weeks of gestation
a spontaneous loss of a clinical pregnancy after 8 weeks but before 22 completed weeks of gestational age, in which the embryo(s) or fetus(es) is/are nonviable and is/are not spontaneously absorbed or expelled from the uterus per initiated embryo transfer cycle and per positive hCG
Measured: 22 weeks
Clinical pregnancy rate
a pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy per initiated embryo transfer cycles
Measured: 7 weeks
Ongoing pregnancy rate
the number of pregnancies after 20 weeks of gestation per initiated embryo transfer cycle
Measured: 20 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Jun 2019
- Study start25 May 2019
- Primary completion1 Jan 2025
- Study completion1 Jan 2025
Why it stopped: safety
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for MiscarriageStudies 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
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Patients will be randomized to either natural cycle frozen-thawed embryo transfer (group A), or hormonal replacement therapy cycle frozen-thawed embryo transfer (group B).
- Masking
- None (open label)
- Enrolment
- 362 participants (actual)
Sponsor and investigators
- Lead sponsor
- CRG UZ Brussel
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Caroline Roelens, CRG UZ Brussel
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03976544
- Sponsor's protocol ID
- HRT_NC-FET
- Other IDs
- 2018-003156-20, 2018
- Status last verified
- Jan 2025
- First submitted
- 4 Jun 2019
- Last updated
- 28 Jan 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Roelens C, Santos-Ribeiro S, Mackens S, De Vos A, Keymolen K, Verdyck P, De Vos M, Tournaye H, Verpoest W, Blockeel C. The impact of endometrial preparation on pregnancy loss in vitrified-warmed euploid blastocyst transfer cycles: a randomized controlled trial. Hum Reprod. 2026 Jun 1;41(6):910-917. doi: 10.1093/humrep/deag060.
PubMed 42081915
Study at a glance
From the registry record, last updated by the sponsor on 28 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Natural Cycle Versus Hormone Replacement Therapy Cycle for a Frozen-thawed Embryo Transfer in PGT Patients: A Randomized Trial
- ClinicalTrials.gov ID
- NCT03976544
- Acronym / sponsor ID
- HRT_NC-FET
- Conditions
- Miscarriage, Frozen Embryo Transfer, Natural Cycle, Hormone Replacement Therapy Cycle, Preimplantation Genetic Screening, Euploid Embryos
- Keywords
- frozen-thawed embryo transfer, FET, natural cycle, hormone replacement therapy cycle, miscarriage
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: safety
- Enrolment
- 362 participants (actual)
- Lead sponsor
- CRG UZ BrusselUniversity, hospital or other
- Study start
- 25 May 2019 (actual)
- Primary completion
- 1 Jan 2025 (actual)
- Study completion
- 1 Jan 2025 (actual)
- First posted
- 6 Jun 2019 (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.
The aim of the current study is to compare miscarriage rates (before 8 weeks) between a true natural cycle (awaiting spontaneous LH surge) and a hormone replacement therapy cycle prior to blastocyst transfer in preimplantation genetic testing (PGT) patients, with biopsy on day 5 of embryonic development. The advantage of performing the study in PGT patients is the exclusion of aneuploidy as a cause of miscarriage.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Patients will be randomized to either natural cycle frozen-thawed embryo transfer (group A), or hormonal replacement therapy cycle frozen-thawed embryo transfer (group B).
| Arm | Type | Receives |
|---|---|---|
| Natural cycle | No intervention | –Patients are asked to perform a blood sample, with evaluation of serum estradiol (E2), progesterone (P), luteinizing hormone (LH) and follicle stimulating hormone (FSH), on the first or second day of the menstrual cycle. If these serum hormonal values are considered basal for the beginning of the follicular phase, patients are asked to come back on day 10 to 12 of the cycle for blood sample and transvaginal ultrasound scan in order to assess follicular growth. The timing of ovulation is determined based on a combination of ultrasonography features (the presence of a dominant follicle and adequate endometrium) and endocrine hormonal values in serum blood samples. Ovulation is generally defined as an, at least, 180% increase of LH compared to the mean level in the previous 24h. Frozen-warmed blastocyst transfer will take place six days following the spontaneous LH surge. |
| Hormone replacement therapy cycle | Experimental | Drug: Estradiol Valerate, Drug: Micronized progesteronePatients are asked to perform a blood sample, with evaluation of serum estradiol (E2), progesterone (P), luteinizing hormone (LH) and follicle stimulating hormone (FSH) on the first or second day of the menstrual cycle. If these values are considered basal for the beginning of the follicular phase, estrogen supplementation (Estradiol valerate, Progynova® 3x2mg/day) is started to induce proliferation of the endometrium. Blood sample and transvaginal ultrasound are thereafter performed ten to fourteen days later. If the endometrium is considered adequate (generally considered if triple line and above 6,5 mm thickness), embryo transfer is scheduled on the sixth day of progesterone (vaginal micronized progesterone, Utrogestan® 2x200mg twice a day) supplementation. In case of escape spontaneous ovulation embryo transfer will be performed considering the presumable time of ovulation. |
Who may qualify
- Ages
- 18 to 42 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- BMI under 35 kg/m2
- Regular menstrual cycle pattern (i.e. 24-35 days cycle)
- First, second and third ICSI-PGT cycle
- First frozen embryo transfer cycle following a fresh ICSI-PGT attempt
- PGT with trophectoderm biopsy on day 5 of embryonic development
Key exclusion criteria (3 listed)
- Oligo-amenorrhea
- BMI above 35
- Contraindications for the use of hormonal replacement therapy
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 |
|---|---|---|
| Estradiol ValerateAlso: ProgynovaEstradiol valerate will be started in the beginning of the menstrual cycle in order to induce proliferation of the endometrium. | Drug | Hormone replacement therapy cycle |
| Micronized progesteroneAlso: UtrogestanIf the endometrium is considered adequately proliferated, micronized progesterone is administered and frozen-thawed blastocyst transfer will take place on the 6th day of supplementation. | Drug | Hormone replacement therapy cycle |
Primary outcome
Miscarriage rate before 8 weeks of gestation
Time frame: 8 weeks
a spontaneous loss of a clinical pregnancy before 8 weeks of gestational age, in which the embryo(s) is/are nonviable and is/are (not) spontaneously absorbed or expelled from the uterus per initiated embryo transfer cycle and per positive hCG
3 secondary outcomes
Miscarriage rate after 8 weeks of gestation
Time frame: 22 weeks
Clinical pregnancy rate
Time frame: 7 weeks
Ongoing pregnancy rate
Time frame: 20 weeks
Results and safety
The study was stopped early (reason given: safety). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Jan 2025.
- Derived from this study: PubMed 42081915Roelens C, Santos-Ribeiro S, Mackens S, De Vos A, Keymolen K, Verdyck P, De Vos M, Tournaye H, Verpoest W, Blockeel C. The impact of endometrial preparation on pregnancy loss in vitrified-warmed euploid blastocyst transfer cycles: a randomized controlled trial. Hum Reprod. 2026 Jun 1;41(6):910-917. doi: 10.1093/humrep/deag060.
- 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.
The record lists no contact. Use the official record to reach the sponsor.
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 Estradiol Valerate and Micronized progesterone in people with Miscarriage and Frozen Embryo Transfer, run by CRG UZ Brussel at 1 site in Belgium.
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 6 inclusion and 3 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: stopped early, as of the sponsor's last update on 28 Jan 2025. 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 Belgium. 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 was stopped early (reason given: safety). Results are not available in the source record.
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?
Miscarriage rate before 8 weeks of gestation (time frame: 8 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03976544, which also lists 1 linked publication.
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 28 Jan 2025.