Natural Versus Programmed Frozen Embryo Transfer (NatPro)

Pregnancy Related Clinical Trial

— NatPro  

Official title:

Multi-center, Parallel-group, Randomized Controlled Trial of Modified Natural Versus Programmed Cycles for Frozen Embryo Transfers and Their Association With Preeclampsia and Live Births

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04551807
• Other study ID #: IRB00214688
• Status: Recruiting
• Phase: Phase 3
• Start date: September 16, 2020
• Est. completion date: August 31, 2025

Study information

• Verified date: October 2023
• Source: JHSPH Center for Clinical Trials
• Contact: David Shade, JD
• Phone: 410-955-8175
• Email: dshade[@]jhmi.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

NatPro is a two-arm, parallel-group, multi-center, randomized trial in which women undergoing frozen embryo transfer (FET) will be randomized to receive either a modified natural cycle (corpus luteum present) or a programmed cycle (corpus luteum absent).

Description:

NatPro is a two-arm, parallel-group, multi-center, randomized trial in which women undergoing FET will be randomized to receive either a modified natural cycle (corpus luteum present) or a programmed cycle (corpus luteum absent). The study will implement a stratified randomization design to balance the use of pre-implantation genetic testing (PGT) across the two treatment arms. Each participant will have up to 3 FET cycles until live birth occurs, or the participant has no embryos available for transfer. Primary endpoints will be the proportion of women experiencing preeclampsia comparing modified natural to programmed FET among women with viable pregnancy (defined as pregnancy lasting at least 20 weeks) and the cumulative proportion of women having live births in the two arms.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 788
• Est. completion date: August 31, 2025
• Est. primary completion date: April 1, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 41 Years

Eligibility

Inclusion criteria

To be eligible, subjects must meet all these criteria:

• Age 18-39 years at the time that embryos were created if no PGT testing was performed. If PGT testing was performed and indicates that an embryo is euploid, the patient can be included if she was age 18-41 years at the time that the embryo was created.
• Age 18-41 years at the time of randomization as advancing age itself becomes a significant risk for preeclampsia
• Normal uterine cavity as assessed by saline infusion sonohysterogram, hysterosalpingogram, or hysteroscopy within one year of the enrollment visit, and repeated at the discretion of the investigator
• Regular menstrual cycle length (approximately 24-35 days) indicative of ovulatory cycles.
• Willing to undergo elective single embryo transfer
• Body Mass Index <=40
• If Body Mass Index is over 30 or individual has other risk factors for diabetes, normal hemoglobin A1C
• Prior to enrollment, participant will have at least one vitrified blastocyst with euploid result by pre-implantation genetic testing (PGT-A) or at least one vitrified blastocyst of fair or better morphologic quality if no PGT-A results are available.
• Willingness to be randomized to either a modified natural or programmed cycle, with a willingness to administer intramuscular progesterone in oil if assigned to the programmed cycle.
• Normal thyroid stimulating hormone (TSH), according to local laboratory standards (or TSH level with a clinically insignificant abnormality per the site director), within one year of study enrollment and repeated at the discretion of the investigator. Use of thyroid medication is permitted. Exclusion criteria

To be eligible, subjects must not meet any one of these criteria:

• Medical contraindication to pregnancy
• Embryos created using donor oocytes
• Embryo donation
• Gestational carrier
• Reciprocal IVF (one female partner carrying pregnancy, other female partner as source of eggs)
• Fresh embryos created from frozen oocytes. Patients with frozen embryos created from frozen oocytes can be included.
• Recurrent implantation failure defined as no clinical pregnancy with = 2 prior consecutive embryo transfers unless patient also had successful live birth between or after the failed embryo transfers
• Anti-phospholipid antibody syndrome or rheumatologic disease requiring chronic systemic medications
• Uncontrolled diabetes mellitus
• History of >1 pregnancy loss in the second or third trimester
• Uncontrolled hypertension
• Untreated hydrosalpinx (i.e., hydrosalpinx in situ which has not been ligated or removed)
• Mullerian uterine anomaly, if not correctable
• Physician recommendation to perform the embryo transfer outside of the timing specified by the protocol
• Contraindication to any medication which must be used in preparation for the frozen embryo transfer (i.e., estradiol, progesterone, hCG)

Related Conditions & MeSH terms

• Eclampsia
• Pre-Eclampsia
• Pregnancy Related

Intervention

Procedure:
• Modified natural cycle
This treatment protocol is defined as a modified natural cycle as the participant will be instructed to (1) administer human chorionic gonadotropin (hCG) to assist with timing of the embryo transfer and (2) supplement the luteal phase with a low dose of progesterone.
• Programmed cycle
This protocol is designated as programmed because the endometrial development occurs only in association with administration of estradiol and progesterone. No ovulation occurs due to suppression of follicle development by the estradiol and the timing of the transfer is based on the number of days elapsed following initiation of exogenous progesterone.

Locations

Country	Name	City	State
United States	Johns Hopkins	Baltimore	Maryland
United States	Cleveland Clinic Foundation	Beachwood	Ohio
United States	CARE Fertility	Bedford	Texas
United States	Atrium Health	Charlotte	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	Fertility Institute of Hawaii	Honolulu	Hawaii
United States	West Virginia University Center for Reproductive Medicine	Morgantown	West Virginia
United States	University of Oklahoma	Oklahoma City	Oklahoma
United States	Yale	Orange	Connecticut
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Rochester	Rochester	New York
United States	Shady Grove Fertility	Rockville	Maryland
United States	Stanford University	Sunnyvale	California
United States	Boston IVF	Waltham	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
JHSPH Center for Clinical Trials

Country where clinical trial is conducted

United States, 

References & Publications (1)

Baksh S, Casper A, Christianson MS, Devine K, Doody KJ, Ehrhardt S, Hansen KR, Lathi RB, Timbo F, Usadi R, Vitek W, Shade DM, Segars J, Baker VL; NatPro Study Group. Natural vs. programmed cycles for frozen embryo transfer: study protocol for an investigator-initiated, randomized, controlled, multicenter clinical trial. Trials. 2021 Sep 27;22(1):660. doi: 10.1186/s13063-021-05637-3. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Preeclampsia	Frequency of preeclampsia, as defined by American College of Obstetricians and Gynecologists (ACOG) guidelines for hypertensive disorders in pregnancy (Obstetrics & Gynecology 2020;135:e237-e260)	During pregnancy through the post-partum period, according to ACOG guidelines (typically between 20 weeks gestation and 6 weeks post-delivery)