FET Protocols for Infertility

(PREFER Trial)

No longer recruiting at 1 trial location

Overseen By Caroline Zuckerman, BS, RN

Age: 18 - 65

Sex: Female

Trial Phase: Academic

Sponsor: Reproductive Medicine Associates of New Jersey

Must not be taking: Anticoagulants, Antihistamines

Disqualifiers: Hypertension, Uterine defects, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6-8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the best approach for a second frozen embryo transfer (FET Protocol) for individuals facing infertility. It aims to determine if altering the method, or protocol, after an unsuccessful first attempt might improve pregnancy success rates. Participants will be randomly assigned to either repeat the same programmed protocol or try a modified natural protocol. Ideal candidates are those who experienced a failed first attempt with a programmed cycle and still have at least one viable embryo stored.

As an unphased trial, this study provides participants the opportunity to contribute to valuable research that could enhance future fertility treatments.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking all current medications. However, you must discontinue any adjunctive therapies for endometrial proliferation or receptivity, such as anticoagulation and antihistamines, upon enrollment.

What prior data suggests that these FET protocols are safe for infertility treatment?

Research shows that both the programmed FET and modified natural FET methods are generally safe, but they have different aspects to consider. In the programmed FET method, studies suggest a risk of issues with the uterine lining, crucial for pregnancy, and potential problems with the placenta. However, these risks do not seem to affect overall pregnancy success compared to the natural cycle FET.

For the modified natural FET method, research indicates positive results. Patients using this method often experience higher chances of live births and lower chances of miscarriage. A common component of this method is a trigger shot, which helps mature the eggs and is generally well-tolerated.

Both methods are widely used in infertility treatments and are considered safe, with the main differences in specific pregnancy outcomes. Participants in this study can feel confident about the safety of both approaches, though each has its own details. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the FET Protocols for infertility because they explore different approaches to preparing the uterine lining for embryo transfer. The Programmed FET Protocol uses exogenous estrogen and intramuscular progesterone to carefully time and optimize the uterine environment for embryo implantation. Meanwhile, the Modified Natural FET Protocol leverages the body's natural cycle, using a trigger shot of hCG and vaginal progesterone, which might appeal to those looking for a less medication-intensive approach. By comparing these methods, the trial aims to uncover insights that could improve success rates and offer more personalized options for individuals undergoing fertility treatment.

What evidence suggests that these FET protocols could be effective for infertility?

This trial will compare the effectiveness of two frozen embryo transfer (FET) methods for treating infertility: the Programmed FET Protocol and the Modified Natural FET Protocol. Studies have shown that both methods can be effective, with research indicating a clinical pregnancy chance of about 39.7% for either method. Specifically, one study found that programmed protocols have a live birth chance of about 45.9% using frozen embryos. Another study suggested that modified natural FETs achieve similar live birth rates to programmed transfers. These findings indicate that both methods can lead to successful pregnancies, offering options for those seeking fertility treatments. ^{2 6 7 8 9}

Who Is on the Research Team?

Emre U Seli, MD

Principal Investigator

Reproductive Medicine Associates of New Jersey

Are You a Good Fit for This Trial?

This trial is for women aged 18-53 with a BMI of 16-45 kg/m2 who have had one unsuccessful frozen embryo transfer (FET) using a programmed cycle. They must have at least one euploid blastocyst left, regular menstrual cycles or detectable LH surge, and an endometrial thickness ≥7 mm from the last cycle.

Inclusion Criteria

My embryo was tested for genetic normality after January 1, 2017.

My recent tests show a normal uterus.

My first frozen embryo transfer did not result in a successful pregnancy.

Exclusion Criteria

You had a previous failed fertility treatment that resulted in a lost pregnancy or pregnancy occurring outside the uterus.

Patients with an endometrial thickness < 7 mm prior to progesterone start in prior cycle

My embryo was tested before January 1, 2017.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo a second FET transfer attempt with either a programmed or modified natural protocol, including routine FET monitoring and shear wave elastography.

6-8 weeks

Follow-up

Participants are monitored for pregnancy outcomes, including biochemical and clinical pregnancy rates, and obstetrical and neonatal outcomes.

40 weeks

Long-term Follow-up

Participants are monitored for sustained implantation rate and live birth rate.

16-32 weeks post discharge at 8 weeks gestational age

What Are the Treatments Tested in This Trial?

Interventions

• FET Protocol

Trial Overview The study compares two FET protocols in patients needing a second attempt after an initial failure. Participants will be randomly assigned to either repeat the programmed protocol or switch to a modified natural protocol, assessing pregnancy outcomes and uterine flexibility.

How Is the Trial Designed?

Group I: Programmed FET Protocol Experimental Treatment 1 Intervention

Patients in this arm of the study will proceed with another programmed FET protocol which involves taking exogenous estrogen by mouth to stimulate the uterine lining to grow and develop. Once the lining has reached ≥ 7 mm and an endometrial pattern of type 1 or type 2, intramuscular progesterone in oil (50mg/ml daily) will be started at 8am on the morning that progesterone is initiated and continued per routine.

Group II: Modified Natural FET Protocol Experimental Treatment 1 Intervention

Following development of at least one dominant follicle and endometrial proliferation ≥ 7 mm during cycle monitoring, patient will undergo administration of human chorionic gonadotropin (hCG) trigger shot followed by initiation of vaginal progesterone administration in accordance with institutional protocols.

Who Is Running the Clinical Trial?

Reproductive Medicine Associates of New Jersey

Lead Sponsor

Trials

56

Recruited

38,200+

Published Research Related to This Trial

In a study of 796 women undergoing reproductive surgery, the overall rate of adverse events (AEs) was 6%, with 12 of these events deemed preventable, highlighting the importance of monitoring for safety in surgical settings.

The duration of surgery was identified as a significant risk factor for AEs, with longer surgeries increasing the likelihood of complications, suggesting that surgical time management could improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcome monitoring in a reproductive surgery unit: a prospective cohort study in 796 patients. Bentz, EK., Imhof, M., Pateisky, N., et al.[2009]

The two new hair transplant designs are reported to be safer than standard methods, potentially reducing the risk of complications during surgery.

These innovative designs aim to provide a more natural appearance for patients, enhancing the aesthetic outcomes of hair transplant procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hair transplant surgery: innovative designs. Norwood, OT., Taylor, BJ.[2019]

A comparison of adverse event reports (AERs) for mifepristone abortions from 2009 to 2010 revealed significant discrepancies, with Cleland et al. documenting 1530 cases while the FDA's FAERS reported only 664 total AERs.

The findings suggest that the FAERS system may be inadequate for accurately assessing the safety of mifepristone abortions, as it reported only a fraction of ongoing pregnancies (95) compared to Cleland's documentation (1158).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mifepristone Adverse Events Identified by Planned Parenthood in 2009 and 2010 Compared to Those in the FDA Adverse Event Reporting System and Those Obtained Through the Freedom of Information Act. Cirucci, CA., Aultman, KA., Harrison, DJ.[2022]

Both Follicular Unit Excision (FUE) and Follicular Unit Transplantation (FUT) are effective methods for harvesting high-quality hair grafts, as confirmed by a comprehensive review of existing literature.

FUE results in less noticeable punctate scars, while FUT leaves a linear scar, allowing patients to choose a method based on their scarring preferences and eligibility.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Old Friend or New Ally: A Comparison of Follicular Unit Transplantation and Follicular Unit Excision Methods in Hair Transplantation. Gupta, AK., Love, RP., Harris, JA.[2021]

In a study of 129 patients undergoing frozen embryo transfer, the modified natural cycle (mNC) protocol showed a higher clinical pregnancy rate (65.2%) compared to the artificial endometrial preparation (AC) and natural cycle (NC) protocols, although this difference was not statistically significant.

The implantation rate was significantly higher in the mNC group (50%) compared to the AC (34%) and NC (12%) groups, suggesting that mNC may be more effective for endometrial preparation in FET cycles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modified natural protocol seems superior to natural and artificial protocols for preparing the endometrium in frozen embryo transfer cycles. Isikoglu, M., Aydinuraz, B., Avci, A., et al.[2021]

The method described for hair transplanting involves creating recipient sites that mimic natural hair directions and angles, which helps achieve a more natural appearance.

Using grafts with multiple follicular units can enhance the density of the transplanted hair without accelerating the loss of existing hair in the recipient area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recipient area hair direction and angle in hair transplanting. Unger, WP.[2022]

From 2013 to 2016, the incidence of adverse events (AEs) in Swedish hospitals decreased from 13.1% to an average of 11.4%, indicating improvements in patient safety during this period.

Preventable AEs were significantly more common (84% more) in patients cared for in inappropriate units ('off-site'), highlighting the importance of proper patient placement and the substantial economic burden of these events, which accounted for 13%-14% of total hospital care costs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence of adverse events in Sweden during 2013-2016: a cohort study describing the implementation of a national trigger tool. Nilsson, L., Borgstedt-Risberg, M., Soop, M., et al.[2019]

A study analyzing 4703 insulin and 6487 somatropin adverse event reports revealed inconsistent reporting practices and a lack of manufacturer identifiability, which could complicate the attribution of adverse events to specific biologics or their biosimilars.

The findings highlight the urgent need for clear biosimilar naming conventions to enhance drug safety monitoring and ensure accurate reporting of adverse events as more biosimilars enter the market.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluating AE Reporting of Two Off-Patent Biologics to Inform Future Biosimilar Naming and Reporting Practices. Stergiopoulos, S., Getz, K.[2018]

Follicular unit transplantation (FUT) is a highly refined hair restoration technique that uses microscopic dissection to transplant hair in natural groupings, resulting in outcomes that closely resemble natural hair growth.

FUT is recognized for providing natural-looking hairlines with good density and low recovery time, but the success of the procedure heavily relies on the skill and planning of the technician performing it.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Follicular unit transplantation. Rousso, DE., Presti, PM.[2008]

Follicular Unit Transplantation (FUT) effectively moves hair from donor to recipient areas while mimicking natural hair patterns and minimizing damage to hair follicles.

By following established standards for dissection and implantation, surgeons can reliably achieve specific aesthetic outcomes with FUT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Follicular unit transplantation: dissecting and planting techniques. Harris, JA.[2006]

A new framework for monitoring adverse events (AEs) in pregnancy trials has been developed, which includes specific definitions and severity grading for both maternal and fetal AEs, enhancing safety assessments for drugs and interventions.

The framework was created through a comprehensive literature review and consensus from an international group of experts, resulting in 12 maternal and 19 fetal AE definitions that can be systematically applied in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of standard definitions and grading for Maternal and Fetal Adverse Event Terminology. Spencer, RN., Hecher, K., Norman, G., et al.[2022]

The modified natural cycle (mNC) protocol for frozen embryo transfer (FET) resulted in significantly higher clinical pregnancy rates (CPR) and live birth rates (LBR) compared to both natural cycle (NC) and programmed/artificial cycle (AC) protocols, with LBRs of 36.3% for mNC versus 32.3% for NC and 26.6% for AC.

There were no significant differences in outcomes between the NC and AC protocols, indicating that both methods are equally effective, but mNC is the preferred option for better success rates in women undergoing FET.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endometrial preparation methods prior to frozen embryo transfer: A retrospective cohort study comparing true natural cycle, modified natural cycle and artificial cycle. Mensing, L., Dahlberg, ES., Bay, B., et al.[2022]

In a study of 490 frozen embryo transfer cycles, the modified natural cycle (mNC) and artificial cycle (AC) protocols showed comparable rates of live births and clinical pregnancies, indicating that both methods are effective for embryo transfer.

However, for patients undergoing double embryo transfers, the mNC protocol resulted in significantly higher live birth (48% vs. 31.4%) and clinical pregnancy rates (53.9% vs. 38.8%) compared to the AC protocol, suggesting mNC may be a better option in these cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Live birth after frozen-thawed embryo transfer: which endometrial preparation protocol is better? Sahin, G., Acet, F., Calimlioglu, N., et al.[2021]

In a study of 428 patients undergoing 493 frozen-thawed blastocyst transfers, the modified natural cycle frozen embryo transfer (NC-FET) protocol showed comparable clinical pregnancy rates (54.3%) and delivery rates (47.2%) to the down-regulated hormonally controlled frozen embryo transfer (HC-FET) protocol (52.5% and 43.6%, respectively).

Factors such as patient age, number of blastocysts transferred, and the year of transfer significantly influenced clinical pregnancy outcomes, indicating that while both protocols are effective, individual patient characteristics play a crucial role in success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modified natural cycle for embryo transfer using frozen-thawed blastocysts: A satisfactory option. Le, QV., Abhari, S., Abuzeid, OM., et al.[2022]

Most U.S. Assisted Reproductive Technology (ART) clinics offer natural cycle frozen embryo transfer (NC-FET), but only a small percentage of cycles utilize this method, with 76% of clinics reporting that less than 25% of their FET cycles use NC-FET for endometrial preparation.

Common barriers to offering NC-FET include concerns about timing predictability and increased workload for staff, with 65% of clinics expressing a positive attitude towards NC-FET despite these challenges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Natural cycle frozen embryo transfer: a survey of current assisted reproductive technology practices in the U.S. Lee, JC., Calzada-Jorge, NS., Hipp, HS., et al.[2023]

Citations

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Reproductive and Obstetric Outcomes Following a Natural ... Results: The overall clinical pregnancy rate/embryo transfer was 39.7%, the miscarriage rate was 10.1%, and the live birth rate/embryo transfer ...

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Cycle management in frozen embryo transfer: the best of ... According to the latest European Society of Human Reproduction and Embryology data, FET cycles now account for 36.3% of all ART treatments, with this number ...

3. fertstert.org fertstert.org/article/S0015-0282%2823%2900148-6/fulltext

Modified natural and optimized programmed frozen ... Modified natural and optimized programmed frozen embryo transfers have equivalent live birth rates: an analysis of 6,682 cycles - Fertility and ...

4. academic.oup.com academic.oup.com/hropen/article/2025/3/hoaf047/8203478

Pregnancy and perinatal outcomes after modified natural ... The adjusted models included the following variables: maternal age and BMI, parity, infertility duration and cause, insemination method, the number of oocytes ...

5. nature.com nature.com/articles/s41598-024-80356-8

Improved clinical pregnancy rates in natural frozen-thawed ... Pregnancy outcomes were compared between the groups. The ovulation prediction model exhibited 93.85% and 92.89% matching rates with the REI ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12343029/

Pregnancy and perinatal outcomes after modified natural ... There is growing evidence concerning the optimal timing for triggering final oocyte maturation during IVF ovarian stimulation cycles to obtain mature oocytes.

7. sciencedirect.com sciencedirect.com/science/article/pii/S1701216325001665

Comparison of Pregnancy Outcomes in Ovulatory Frozen ... Ovulatory FET cycles, whether triggered or not, result in significantly higher ongoing pregnancy rates and lower miscarriage rates compared to non-ovulatory ...

8. frontiersin.org frontiersin.org/journals/medicine/articles/10.3389/fmed.2021.691428/full

Is Human Chorionic Gonadotropin Trigger Beneficial for ... Our findings show that the NC-FET without the hCG trigger had a higher incidence of clinical pregnancy and live birth than the mNC-FET.

9. tandfonline.com tandfonline.com/doi/full/10.1080/09513590.2025.2533481

The science of frozen embryo transfer, is modified natural ... Recent studies have shown that patients undergoing FET in natural or modified natural cycles have better live birth rates, lower rates of miscarriages, lower ...