Natural Versus Programmed Frozen Embryo Transfer (NatPro)

NCT04551807 | Active Not Recruiting Phase 3 DMC

• 1 other identifier: IRB00214688
• Study Type: interventional
• Target: 788
• Locations: 1 country
• Sites: 15

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).

Conditions

Pregnancy Related; Pre-Eclampsia

Keywords

frozen embryo transfer; infertility; in vitro fertilization

Outcome Measures

Primary Outcomes (1)

• 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)

Study Arms (2)

Modified natural cycle

ACTIVE COMPARATOR

corpus luteum present

Procedure: Modified natural cycle

Programmed cycle

ACTIVE COMPARATOR

corpus luteum absent

Procedure: Programmed cycle

Interventions

Modified natural cycle PROCEDURE

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.

Modified natural cycle

Programmed cycle PROCEDURE

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.

Programmed cycle

Eligibility Criteria

• Age: 18 Years - 41 Years
• Gender Eligibility Details: Women attempting to get pregnant using frozen embryos
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• JHSPH Center for Clinical Trials: lead

Study Sites (15)

University of California San Francisco

San Francisco, California, 94158, United States

Location

Stanford University

Sunnyvale, California, 94087, United States

Location

Yale

Orange, Connecticut, 06477, United States

Location

Fertility Institute of Hawaii

Honolulu, Hawaii, 96814, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Johns Hopkins

Baltimore, Maryland, 21093, United States

Location

Shady Grove Fertility

Rockville, Maryland, 20850, United States

Location

Boston IVF

Waltham, Massachusetts, 02451, United States

Location

University of Rochester

Rochester, New York, 14642, United States

Location

Atrium Health

Charlotte, North Carolina, 28203, United States

Location

Cleveland Clinic Foundation

Beachwood, Ohio, 44122, United States

Location

University of Oklahoma

Oklahoma City, Oklahoma, 73104, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

CARE Fertility

Bedford, Texas, 76022, United States

Location

West Virginia University Center for Reproductive Medicine

Morgantown, West Virginia, 26505, United States

Location

Related 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.

  PMID: 34579768 BACKGROUND

MeSH Terms

Conditions

Pre-Eclampsia; Infertility

Condition Hierarchy (Ancestors)

Hypertension, Pregnancy-Induced; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Study Officials

• Valerie Baker, MD

  Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine

  PRINCIPAL INVESTIGATOR

• James Segars, MD

  Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 27, 2020
• First Posted: September 16, 2020
• Study Start: September 16, 2020
• Primary Completion: February 1, 2026
• Study Completion: April 1, 2026
• Last Updated: May 16, 2025

Record last verified: 2025-05

Locations

US (15)