Clinical trial NCT04551807: Natural Versus Programmed Frozen Embryo Transfer (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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Pregnancy Related
Pre-Eclampsia
Keywords: frozen embryo transfer
infertility
in vitro fertilization
Lead sponsor: JHSPH Center for Clinical Trials
Sponsor class: OTHER
First posted: 2020-09-16
Enrollment: 788
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 41
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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).

Detailed 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Preeclampsia
timeFrame: During pregnancy through the post-partum period, according to ACOG guidelines (typically between 20 weeks gestation and 6 weeks post-delivery)
Secondary outcomes:
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Sunnyvale
country: United States
facility: Stanford University
state: California
city: Orange
country: United States
facility: Yale
state: Connecticut
city: Honolulu
country: United States
facility: Fertility Institute of Hawaii
state: Hawaii
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins
state: Maryland
city: Rockville
country: United States
facility: Shady Grove Fertility
state: Maryland
city: Waltham
country: United States
facility: Boston IVF
state: Massachusetts
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Charlotte
country: United States
facility: Atrium Health
state: North Carolina
city: Beachwood
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma
state: Oklahoma
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Bedford
country: United States
facility: CARE Fertility
state: Texas
city: Morgantown
country: United States
facility: West Virginia University Center for Reproductive Medicine
state: West Virginia
Study officials:
affiliation: Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine
name: Valerie Baker, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine
name: James Segars, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.