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Pregnancy RelatedPhase 3NatProNCT04551807

Natural Versus Programmed Frozen Embryo Transfer (NatPro)

A Phase 3 study testing Modified natural cycle and Programmed cycle in people with Pregnancy Related and Pre-Eclampsia, run by JHSPH Center for Clinical Trials at 15 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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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). Read more about this study

Who is it for?
Ages 18 to 41 years, women onlyHealthy volunteers can take part
Conditions the study is for
Pregnancy Related, Pre-Eclampsia
What is being tested?
Modified natural cycle and Programmed cycle
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
788 participants
Where
15 sitesUnited States
Study dates
16 Sep 2020to 1 Apr 2026
Phase
Phase 3
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 41 years
  • Women only
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • 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
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  • 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.

Who cannot join

  • 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)
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  • 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)

Trial locations and contacts

15 sites in 1 country.

15 sites in 1 country

United States15 sites

  • Johns Hopkins

    Baltimore, Maryland, 21093

  • Cleveland Clinic Foundation

    Beachwood, Ohio, 44122

  • CARE Fertility

    Bedford, Texas, 76022

  • Atrium Health

    Charlotte, North Carolina, 28203

  • Northwestern University

    Chicago, Illinois, 60611

  • Fertility Institute of Hawaii

    Honolulu, Hawaii, 96814

  • West Virginia University Center for Reproductive Medicine

    Morgantown, West Virginia, 26505

  • University of Oklahoma

    Oklahoma City, Oklahoma, 73104

  • Yale

    Orange, Connecticut, 06477

  • University of Pennsylvania

    Philadelphia, Pennsylvania, 19104

  • University of Rochester

    Rochester, New York, 14642

  • Shady Grove Fertility

    Rockville, Maryland, 20850

  • University of California San Francisco

    San Francisco, California, 94158

  • Stanford University

    Sunnyvale, California, 94087

  • Boston IVF

    Waltham, Massachusetts, 02451

Other trials in United States

About this study

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

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).

Read the 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.

Being tested
Modified natural cycle, Programmed cycle
Keywords
frozen embryo transfer, infertility, in vitro fertilization
Medical subject headings
Pre-Eclampsia, Infertility

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Modified natural cycleProcedure or surgery

    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 cycleProcedure or surgery

    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.

Study groups in NCT04551807
Study groupRoleWhat they receive
Modified natural cycleActive comparatorcorpus luteum present
Receives: Procedure: Modified natural cycle
Programmed cycleActive comparatorcorpus luteum absent
Receives: Procedure: Programmed cycle

What is being measured

The primary outcome is the main question the study is designed to answer.

  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)

    Measured: During pregnancy through the post-partum period, according to ACOG guidelines (typically between 20 weeks gestation and 6 weeks post-delivery)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 Sep 2020
  2. Study start16 Sep 2020
  3. Primary completion1 Feb 2026 (estimated)
  4. Study completion1 Apr 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
788 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04551807
Sponsor's protocol ID
IRB00214688
Acronym
NatPro
Status last verified
May 2025
First submitted
27 Aug 2020
Last updated
16 May 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • 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.

    PubMed 34579768

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Modified natural cycle and Programmed cycle in people with Pregnancy Related and Pre-Eclampsia, run by JHSPH Center for Clinical Trials at 15 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 16 May 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 15 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Preeclampsia (time frame: During pregnancy through the post-partum period, according to ACOG guidelines (typically between 20 weeks gestation and 6 weeks post-delivery)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04551807, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 May 2025.

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