IVFPhase 4NCT06181305
Endometrial Preparation in Frozen Embryo Transfer Cycles
A Phase 4 study testing estradiol valerate and letrozole and letrozole 2,5 mg tablet in people with IVF, run by Rahem Fertility Center at 1 site in Egypt.
Trial summary
In order to get optimal pregnancy rates after frozen embryo transfer (FET), the embryo stage and endometrium should be synchronized. Endometrial preparation is done by either natural, artificial (Hormonal replacement therapy HRT) , modified natural methods or mild ovarian stimulation. Read more about this study
- Who is it for?
- Ages 18 to 37 years, women only
- Conditions the study is for
- IVF
- What is being tested?
- estradiol valerate and letrozole and letrozole 2,5 mg tablet
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 210 participants
- Where
- 1 siteEgypt
- Study dates
- 24 Feb 2024to 25 Dec 2024
- 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 37 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- Women aged between 18 and 37 years with either regular cycles or oligomenorrhoea or amenorrhoea.
- Women undergoing FET cycles.
- Participants should have at least one good-quality blastocyst available for vitrification and also for transfer after warming.
- Participants having optimal endometrium before starting luteal phase support
Who cannot join
- Women who will refuse to participate in in the study.
- Women who will not reach the optimal endometrium.
- Participants that don't have at least one good-quality blastocyst for transfer after warming.
- PGT embryos will be excluded.
Trial locations and contacts
1 site in 1 country.
Egypt1 site, 1 recruiting
- Recruiting
Rahem fertility center
Zagazig, 44511
Eman El-gindy, MD,PhD, 00201227491143, eman_elgindy2013@hotmail.com
Noha Moustafa El hibishy, MSc, 00201067411131, nohaesmaeelobgyn@yahoo.com
About this study
Official title: Hormonal Replacement Therapy Plus Letrozole Incorporation Versus Letrozole Mild Ovarian Stimulation in Endometrial Preparation for Frozen Embryo Transfer: A Randomised Controlled Trial
In order to get optimal pregnancy rates after frozen embryo transfer (FET), the embryo stage and endometrium should be synchronized. Endometrial preparation is done by either natural, artificial (Hormonal replacement therapy HRT) , modified natural methods or mild ovarian stimulation. HRT cycle has a better schedualization however, there are some reports about higher rates of miscarriage, pregnancy induced hypertension (PIH) and preeclampsia (PET) in HRT cycles. A recent study has found that incorporation of the aromatase inhibitor (letrozole) to HRT cycles was associated with better FET outcomes in comparison to hormonal replacement therapy cycles alone. Meanwhile, mild ovarian stimulation protocol can be done either by oral drugs like letrozole or by letrozole plus gonadotropins . So this study aims to compare the reproductive outcomes in two endometrial preparation protocols for frozen embryo transfer cycles; letrozole mild ovarian stimulation versus HRT plus letrozole incorporation.
Read the detailed description
In order to get optimal pregnancy rates after frozen embryo transfer (FET), the embryo stage and endometrium should be synchronized. This can be done by hormonal replacement therapy (HRT), natural cycles (NC), modified natural cycles or mild ovarian stimulation. In hormonal replacement therapy cycle, estrogen and progesterone are sequentially given to resemble the hormonal course of the natural cycle . Hormonal replacement therapy cycle has a better schedualization and is used for patients with irregular cycles as polycystic ovary syndrome ( PCOS). However, there are some reports about higher rates of miscarriage, pregnancy induced hypertension (PIH) and preeclampsia (PET) in HRT cycles.
A recent study has found that incorporation of the aromatase inhibitor (letrozole) to HRT cycles was associated with better FET outcomes in comparison to HRT cycles alone. Ongoing pregnancy rate (OPR) was higher in HRT plus letrozole group than HRT only group.
Letrozole is a third-generation aromatase inhibitor that leads to mono-ovulatory cycles with short half-life . Miller and his colleagues found that letrozole increased Integrin expression and improved pregnancy and implantation rates among women with endometrial receptivity defects . Another study found that ovarian stimulation with letrozole was associated with increase in the expression of uterine receptivity markers including integrin, leukemia inhibitory factor, and L-selectin.
- Conditions
- IVF
- Being tested
- estradiol valerate and letrozole, letrozole 2,5 mg tablet
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
estradiol valerate and letrozoleDrug
hormone replacement therapy by estradiol valerate plus letrozole incorporation .
letrozole 2,5 mg tabletDrug
mild ovarian stimulation
| Study group | Role | What they receive |
|---|---|---|
| Group A (HRT plus letrozole incorporation) | Experimental | Exogenous oestradiol in the form of 2 mg oral oestradiol valerate , three times daily will be started on the 2nd or 3rd day of the cycle. Tri-laminar endometrium of ≥ 9 mm will be the targeted cut-off. If the endometrium does not yet reach the target, oestradiol supplementation will be continued with serial US assessment until the targeted cut-off will be reached. Upon reaching the target endometrium, oral letrozole tablets 2.5 mg will be started twice daily for 5 days only with continuation of 6 mg daily oestradiol supplementation. Then, daily intramuscular progesterone in oil (100 mg intramuscular progesterone) will be started once per day with continuation of 6 mg oestradiol
interventions:
Drug:estradiol valertae
Drug :letrozole 2.5 mg tablet Receives: Drug: estradiol valerate and letrozole |
| Group B (Letrozole mild ovarian stimulation) | Active comparator | Oral letrozole 2.5-5 mg daily on cycle day(3-7) will be added . TVS will be performed from cycle day 8-10 to make sure that a dominant follicle has been recruited with the endometrium thickness ≥ 7 mm . Upon reaching the dominant follicle (18-20mm) , endometrial thickness will be measured on the day of ovulation trigger and blood sample will be withdrawn from each patient for assessment of E2 , P4 and LH levels. Patients with low LH level , high E2 level , low P4 level (<1 ng/ml) will continue in the RCT; 10,000unit HCG will be injected as ovulation trigger
intervention :
Drug :letrozole 2.5mg tablet
procedure: on the day of ovulation trigger blood sample will be withdrawn from each patient for assessment of E2 , P4 and LH levels. Receives: Drug: letrozole 2,5 mg tablet |
What is being measured
The primary outcome is the main question the study is designed to answer.
ongoing pregnancy rate (OPR)
Number of pregnant women with viable fetus at 12 weeks gestation per woman randomized
Measured: 12 weeks
Secondary outcomes (7)
Clinical pregnancy rate (CPR)
Number of gestational sacs with evident fetal pulsations per woman randomized,ectopic pregnancy is also includded pregnancy is aslo included
Measured: 5 weeks after embryo transfer
Ectopic pregnancy
pregnancy outside the uterine cavity diagnosed by ultrasound ,surgical visualization or histopathology
Measured: 7 week
Miscarriage rate
Number of miscarriages per woman with positive pregnancy tests
Measured: 12 weeks
Implantation rate
Number of gestational sac recognized by ultrasound in uterus 3 weeks after embryo transfer
Measured: 21 days after embryo transfer
live birth rate
The complete expulsion or extraction from a woman of a product of fertilization,after 22 complete weeks of gestational age;which,after such separation,breathes or shows any other evidence of life,such as heart beat,umblical cord pulsation or definite movement of voluntary muscles,irrespective of whether the umblical cord has been cut or the placenta is attached.A birth weight of 500 grams or more can be used if gestational age is unknown.Live births refer to the individual newborn ;for example,a twin delivery represents two live births
Measured: 22 completed weeks of gestational age
Number of participants with Hypertensive disorders of pregnancy
gestational hypertension or preeclampsia
Measured: 20 weeks gestation till postpartum
Number of participants with Large for gestational age
A birth weight greater than the 90th centile of the sex-specific birth weight for a given gestational age reference
Measured: from gestation till delivery
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Dec 2023
- Study start24 Feb 2024
- Primary completion25 Nov 2024 (estimated)
- Study completion25 Dec 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for IVFStudies 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
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 210 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Rahem Fertility Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Eman Elgindy, Rahem Fertility Center
- Investigators
- Eman El-gindy, MD,PhD, Principal investigator, Rahem Fertility Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06181305
- Sponsor's protocol ID
- endometrial preparation
- Status last verified
- Feb 2024
- First submitted
- 12 Dec 2023
- Last updated
- 26 Feb 2024
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Elgindy EA, Abdelghany AA, Sibai AbdAlsalam H, Mostafa MI. The novel incorporation of aromatase inhibitor in hormonal replacement therapy cycles: a randomized controlled trial. Reprod Biomed Online. 2022 Apr;44(4):641-649. doi: 10.1016/j.rbmo.2021.10.025. Epub 2021 Dec 20.
PubMed 35288021Ezoe K, Fukuda J, Takeshima K, Shinohara K, Kato K. Letrozole-induced endometrial preparation improved the pregnancy outcomes after frozen blastocyst transfer compared to the natural cycle: a retrospective cohort study. BMC Pregnancy Childbirth. 2022 Nov 7;22(1):824. doi: 10.1186/s12884-022-05174-0.
PubMed 36344952An BGL, Chapman M, Tilia L, Venetis C. Is there an optimal window of time for transferring single frozen-thawed euploid blastocysts? A cohort study of 1170 embryo transfers. Hum Reprod. 2022 Nov 24;37(12):2797-2807. doi: 10.1093/humrep/deac227.
PubMed 36305795Mumusoglu S, Polat M, Ozbek IY, Bozdag G, Papanikolaou EG, Esteves SC, Humaidan P, Yarali H. Preparation of the Endometrium for Frozen Embryo Transfer: A Systematic Review. Front Endocrinol (Lausanne). 2021 Jul 9;12:688237. doi: 10.3389/fendo.2021.688237. eCollection 2021.
PubMed 34305815Zhang J, Liu H, Wang Y, Mao X, Chen Q, Fan Y, Xiao Y, Kuang Y. Letrozole use during frozen embryo transfer cycles in women with polycystic ovary syndrome. Fertil Steril. 2019 Aug;112(2):371-377. doi: 10.1016/j.fertnstert.2019.04.014. Epub 2019 May 21.
PubMed 31126712Godiwala P, Makhijani R, Bartolucci A, Grow D, Nulsen J, Benadiva C, Grady J, Engmann L. Pregnancy outcomes after frozen-thawed embryo transfer using letrozole ovulation induction, natural, or programmed cycles. Fertil Steril. 2022 Oct;118(4):690-698. doi: 10.1016/j.fertnstert.2022.06.013. Epub 2022 Jul 19.
PubMed 35863997Lawrenz B, Melado L, Fatemi HM. Frozen embryo transfers in a natural cycle: how to do it right. Curr Opin Obstet Gynecol. 2023 Jun 1;35(3):224-229. doi: 10.1097/GCO.0000000000000862. Epub 2023 Mar 14.
PubMed 36924405
Study at a glance
From the registry record, last updated by the sponsor on 26 Feb 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Hormonal Replacement Therapy Plus Letrozole Incorporation Versus Letrozole Mild Ovarian Stimulation in Endometrial Preparation for Frozen Embryo Transfer: A Randomised Controlled Trial
- ClinicalTrials.gov ID
- NCT06181305
- Acronym / sponsor ID
- endometrial preparation
- Conditions
- IVF
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 210 participants (estimated)
- Lead sponsor
- Rahem Fertility CenterUniversity, hospital or other
- Study start
- 24 Feb 2024 (actual)
- Primary completion
- 25 Nov 2024 (estimated)
- Study completion
- 25 Dec 2024 (estimated)
- First posted
- 26 Dec 2023 (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.
In order to get optimal pregnancy rates after frozen embryo transfer (FET), the embryo stage and endometrium should be synchronized. Endometrial preparation is done by either natural, artificial (Hormonal replacement therapy HRT) , modified natural methods or mild ovarian stimulation. HRT cycle has a better schedualization however, there are some reports about higher rates of miscarriage, pregnancy induced hypertension (PIH) and preeclampsia (PET) in HRT cycles. A recent study has found that incorporation of the aromatase inhibitor (letrozole) to HRT cycles was associated with better FET outcomes in comparison to hormonal replacement therapy cycles alone. Meanwhile, mild ovarian stimulation protocol can be done either by oral drugs like letrozole or by letrozole plus gonadotropins . So this study aims to compare the reproductive outcomes in two endometrial preparation protocols for frozen embryo transfer cycles; letrozole mild ovarian stimulation versus HRT plus letrozole incorporation.
Detailed description
In order to get optimal pregnancy rates after frozen embryo transfer (FET), the embryo stage and endometrium should be synchronized. This can be done by hormonal replacement therapy (HRT), natural cycles (NC), modified natural cycles or mild ovarian stimulation. In hormonal replacement therapy cycle, estrogen and progesterone are sequentially given to resemble the hormonal course of the natural cycle . Hormonal replacement therapy cycle has a better schedualization and is used for patients with irregular cycles as polycystic ovary syndrome ( PCOS). However, there are some reports about higher rates of miscarriage, pregnancy induced hypertension (PIH) and preeclampsia (PET) in HRT cycles.
A recent study has found that incorporation of the aromatase inhibitor (letrozole) to HRT cycles was associated with better FET outcomes in comparison to HRT cycles alone. Ongoing pregnancy rate (OPR) was higher in HRT plus letrozole group than HRT only group.
Letrozole is a third-generation aromatase inhibitor that leads to mono-ovulatory cycles with short half-life . Miller and his colleagues found that letrozole increased Integrin expression and improved pregnancy and implantation rates among women with endometrial receptivity defects . Another study found that ovarian stimulation with letrozole was associated with increase in the expression of uterine receptivity markers including integrin, leukemia inhibitory factor, and L-selectin.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Group A (HRT plus letrozole incorporation) | Experimental | Drug: estradiol valerate and letrozoleExogenous oestradiol in the form of 2 mg oral oestradiol valerate , three times daily will be started on the 2nd or 3rd day of the cycle. Tri-laminar endometrium of ≥ 9 mm will be the targeted cut-off. If the endometrium does not yet reach the target, oestradiol supplementation will be continued with serial US assessment until the targeted cut-off will be reached. Upon reaching the target endometrium, oral letrozole tablets 2.5 mg will be started twice daily for 5 days only with continuation of 6 mg daily oestradiol supplementation. Then, daily intramuscular progesterone in oil (100 mg intramuscular progesterone) will be started once per day with continuation of 6 mg oestradiol interventions: Drug:estradiol valertae Drug :letrozole 2.5 mg tablet |
| Group B (Letrozole mild ovarian stimulation) | Active comparator | Drug: letrozole 2,5 mg tabletOral letrozole 2.5-5 mg daily on cycle day(3-7) will be added . TVS will be performed from cycle day 8-10 to make sure that a dominant follicle has been recruited with the endometrium thickness ≥ 7 mm . Upon reaching the dominant follicle (18-20mm) , endometrial thickness will be measured on the day of ovulation trigger and blood sample will be withdrawn from each patient for assessment of E2 , P4 and LH levels. Patients with low LH level , high E2 level , low P4 level (<1 ng/ml) will continue in the RCT; 10,000unit HCG will be injected as ovulation trigger intervention : Drug :letrozole 2.5mg tablet procedure: on the day of ovulation trigger blood sample will be withdrawn from each patient for assessment of E2 , P4 and LH levels. |
Who may qualify
- Ages
- 18 to 37 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- Women aged between 18 and 37 years with either regular cycles or oligomenorrhoea or amenorrhoea.
- Women undergoing FET cycles.
- Participants should have at least one good-quality blastocyst available for vitrification and also for transfer after warming.
- Participants having optimal endometrium before starting luteal phase support
Key exclusion criteria (4 listed)
- Women who will refuse to participate in in the study.
- Women who will not reach the optimal endometrium.
- Participants that don't have at least one good-quality blastocyst for transfer after warming.
- PGT embryos will be excluded.
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 valerate and letrozolehormone replacement therapy by estradiol valerate plus letrozole incorporation . | Drug | Group A (HRT plus letrozole incorporation) |
| letrozole 2,5 mg tabletmild ovarian stimulation | Drug | Group B (Letrozole mild ovarian stimulation) |
Primary outcome
ongoing pregnancy rate (OPR)
Time frame: 12 weeks
Number of pregnant women with viable fetus at 12 weeks gestation per woman randomized
7 secondary outcomes
Clinical pregnancy rate (CPR)
Time frame: 5 weeks after embryo transfer
Ectopic pregnancy
Time frame: 7 week
Miscarriage rate
Time frame: 12 weeks
Implantation rate
Time frame: 21 days after embryo transfer
live birth rate
Time frame: 22 completed weeks of gestational age
Number of participants with Hypertensive disorders of pregnancy
Time frame: 20 weeks gestation till postpartum
Number of participants with Large for gestational age
Time frame: from gestation till delivery
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Feb 2024.
- Background: PubMed 35288021Elgindy EA, Abdelghany AA, Sibai AbdAlsalam H, Mostafa MI. The novel incorporation of aromatase inhibitor in hormonal replacement therapy cycles: a randomized controlled trial. Reprod Biomed Online. 2022 Apr;44(4):641-649. doi: 10.1016/j.rbmo.2021.10.025. Epub 2021 Dec 20.
- Background: PubMed 36344952Ezoe K, Fukuda J, Takeshima K, Shinohara K, Kato K. Letrozole-induced endometrial preparation improved the pregnancy outcomes after frozen blastocyst transfer compared to the natural cycle: a retrospective cohort study. BMC Pregnancy Childbirth. 2022 Nov 7;22(1):824. doi: 10.1186/s12884-022-05174-0.
- Background: PubMed 36305795An BGL, Chapman M, Tilia L, Venetis C. Is there an optimal window of time for transferring single frozen-thawed euploid blastocysts? A cohort study of 1170 embryo transfers. Hum Reprod. 2022 Nov 24;37(12):2797-2807. doi: 10.1093/humrep/deac227.
- Background: PubMed 34305815Mumusoglu S, Polat M, Ozbek IY, Bozdag G, Papanikolaou EG, Esteves SC, Humaidan P, Yarali H. Preparation of the Endometrium for Frozen Embryo Transfer: A Systematic Review. Front Endocrinol (Lausanne). 2021 Jul 9;12:688237. doi: 10.3389/fendo.2021.688237. eCollection 2021.
- Background: PubMed 31126712Zhang J, Liu H, Wang Y, Mao X, Chen Q, Fan Y, Xiao Y, Kuang Y. Letrozole use during frozen embryo transfer cycles in women with polycystic ovary syndrome. Fertil Steril. 2019 Aug;112(2):371-377. doi: 10.1016/j.fertnstert.2019.04.014. Epub 2019 May 21.
- Background: PubMed 35863997Godiwala P, Makhijani R, Bartolucci A, Grow D, Nulsen J, Benadiva C, Grady J, Engmann L. Pregnancy outcomes after frozen-thawed embryo transfer using letrozole ovulation induction, natural, or programmed cycles. Fertil Steril. 2022 Oct;118(4):690-698. doi: 10.1016/j.fertnstert.2022.06.013. Epub 2022 Jul 19.
- Background: PubMed 36924405Lawrenz B, Melado L, Fatemi HM. Frozen embryo transfers in a natural cycle: how to do it right. Curr Opin Obstet Gynecol. 2023 Jun 1;35(3):224-229. doi: 10.1097/GCO.0000000000000862. Epub 2023 Mar 14.
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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.
Eman El-gindy, MD,PhD principal investigator
Rahem Fertility Center
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 letrozole and letrozole 2,5 mg tablet in people with IVF, run by Rahem Fertility Center at 1 site in Egypt.
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 4 inclusion and 4 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: status not confirmed, as of the sponsor's last update on 26 Feb 2024. 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 Egypt. 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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Noha Moustafa El-hibishy, MSc (00201067411131, nohaesmaeelobgyn@yahoo.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
ongoing pregnancy rate (OPR) (time frame: 12 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 NCT06181305, which also lists 7 linked publications.
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 26 Feb 2024.