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Natural Versus Programmed Frozen Embryo Transfer (NatPro) (NatPro)

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ClinicalTrials.gov Identifier: NCT04551807
Recruitment Status : Recruiting
First Posted : September 16, 2020
Last Update Posted : August 4, 2022
Information provided by (Responsible Party):
JHSPH Center for Clinical Trials

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).

Condition or disease Intervention/treatment Phase
Pregnancy Related Pre-Eclampsia Procedure: Modified natural cycle Procedure: Programmed cycle Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 788 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Prevention
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
Actual Study Start Date : September 16, 2020
Estimated Primary Completion Date : April 1, 2024
Estimated Study Completion Date : September 30, 2024

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Active Comparator: Modified natural cycle
corpus luteum present
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.

Active Comparator: Programmed cycle
corpus luteum absent
Procedure: 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.

Primary Outcome Measures :
  1. Preeclampsia [ Time Frame: During pregnancy through the post-partum period, according to ACOG guidelines (typically between 20 weeks gestation and 6 weeks post-delivery) ]
    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)

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 41 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Women attempting to get pregnant using frozen embryos
Accepts Healthy Volunteers:   Yes

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04551807

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Contact: David Shade, JD 410-955-8175 dshade@jhmi.edu

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United States, California
Stanford University Recruiting
Sunnyvale, California, United States, 94087
Contact: Alma Gonzalez    408-688-9892    agonlez@stanford.edu   
Principal Investigator: Ruth Lathi, MD         
United States, Maryland
Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21093
Contact: Mindy Christianson, MD    410-583-2761    mchris21@jhmi.edu   
Contact: Bhuchitra Singh    4106142000    bsingh10@jhmi.edu   
Principal Investigator: Mindy Christianson, MD         
Shady Grove Fertility Recruiting
Rockville, Maryland, United States, 20850
Contact: Clinical Research Team    301-545-1423    sgfclinicalresearchteam@sgfertility.com   
Contact: Tasha Newsome    301-545-1289    Tasha.Newsome@sgfertility.com   
Principal Investigator: Kate Devine, MD         
United States, New York
University of Rochester Recruiting
Rochester, New York, United States, 14642
Contact: Lynda Kochman    585-275-0250    lynda_kochman@urmc.rochester.edu   
Principal Investigator: Wendy Vitek, MD         
United States, North Carolina
Atrium Health Recruiting
Charlotte, North Carolina, United States, 28203
Contact: Mary Andrews    704-953-4832    mary.andrews@atriumhealth.org   
Contact: Gretchen Hoelscher       gretchen.hoelscher@atriumhealth.org   
Principal Investigator: Rebecca Usadi, MD         
United States, Oklahoma
University of Oklahoma Recruiting
Oklahoma City, Oklahoma, United States, 73104
Contact: Michelle Starkey-Scruggs    405-271-9204    Michelle-StarkeyScruggs@ouhsc.edu   
Principal Investigator: Karl Hansen, MD         
United States, Pennsylvania
University of Pennsylvania Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Andrea Morley    215-615-4202    Andrea.Morley@pennmedicine.upenn.edu   
Principal Investigator: Christos Coutifaris         
United States, Texas
CARE Fertility Recruiting
Bedford, Texas, United States, 76022
Contact: Aracely Casillas    817-540-1157    aracelyc@embryo.net   
Principal Investigator: Kevin Doody, MD         
United States, West Virginia
West Virginia University Center for Reproductive Medicine Recruiting
Morgantown, West Virginia, United States, 26505
Contact: Karen Merryweather    304-598-3100    merrymank@wvumedicine.org   
Principal Investigator: Ryan Heitmann, MD         
Sponsors and Collaborators
JHSPH Center for Clinical Trials
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Principal Investigator: 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
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: JHSPH Center for Clinical Trials
ClinicalTrials.gov Identifier: NCT04551807    
Other Study ID Numbers: IRB00214688
First Posted: September 16, 2020    Key Record Dates
Last Update Posted: August 4, 2022
Last Verified: August 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by JHSPH Center for Clinical Trials:
frozen embryo transfer
in vitro fertilization
Additional relevant MeSH terms:
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Hypertension, Pregnancy-Induced
Pregnancy Complications