Surveillance and Treatment to Prevent Fetal Atrioventricular Block Likely to Occur Quickly (STOP BLOQ)

July 18, 2023 updated by: NYU Langone Health
Fetal complete (i.e., third degree, 3°) atrioventricular block (AVB), identified in the 2nd trimester of pregnancy in an otherwise normally developing heart, is almost universally associated with maternal anti-Ro autoantibodies and results in death in a fifth of cases. To date treatment of 3° AVB has been ineffective in restoring normal rhythm (NR) which may be because current surveillance is limited to once- weekly fetal echocardiograms. It is hypothesized that there may be a vital transition period of several hours in which incomplete block (2° AVB) may be successfully treated avoiding fully advanced irreversible 3° AVB. To optimize the likelihood of timely detection of the transition period this study comprises three steps: 1) to risk stratify for high titer anti-Ro antibodies, which are necessary but not sufficient to develop fetal AVB; 2) to empower mothers to identify 2° AVB by using fetal heart rate and rhythm monitoring (FHRM) at home, and 3) to rapidly treat mothers who detect an abnormality by monitoring with an urgent echocardiogram that confirms 2° AVB with the hope of reversing 2° AVB before it becomes permanent (3° AVB). In addition, it will be determined if FHRM reduces the need for weekly echoes. Although mothers with low titer anti-Ro will not be continued in Step 2 and therefore not followed by FHRM, birth ECGs will be collected to confirm that low titer antibodies do not confer risk. It is anticipated that this study will provide an evidenced based surveillance strategy for those mothers at high risk of having a child with 3° AVB.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Fetal complete (3°) atrioventricular block (AVB), identified in the 2nd trimester in an otherwise normally developing heart, is almost universally associated with maternal anti-Ro autoantibodies, which transcytose the placenta via the trophoblastic IgG receptor, FcγRn. The burden of 3° AVB is considerable: perinatal mortality of 18% exceeds that for all non-cardiac congenital anomalies combined, and almost all survivors require lifelong cardiac pacing with its associated complications. It has been speculated that full expression of conduction disease occurs by sequential fetal progression from normal rhythm (NR) to 1° AVB [prolonged AV interval assessed by echocardiogram (echo)], to 2° AVB (irregular cardiac rhythm or bradycardia), culminating in 3° AVB. Fetal heart rate and rhythm monitoring (FHRM) suggests a time interval of ~12 hours for the transition from NR to 3° AVB, albeit the culprit biologic processes (inflammation leading to fibrosis) likely initiate prior to clinical detection. Anecdotal evidence suggests this transition period, marked by an irregular rhythm and/or bradycardia, may be the only window of opportunity for anti-inflammatory treatment to restore NR.

A barrier to preventing progression to 3° AVB is the absence of a technique to accurately surveil for the precipitate transition from NR to 3° AVB. Surveillance limited to weekly echos (current standard of care) may be too infrequent to detect this transition period when treatment is most likely to be effective. We have now obviated this obstacle and shown that ambulatory FHRM by the mother at home with confirmation of abnormal findings by echo is not only feasible but may afford rapid treatment restoring NR. Combining results from studies comprising 275 anti-Ro+ pregnancies, 87% completed monitoring with a false positive rate of 5%. In 4 cases of 2° AVB identified by FHRM and treated <12h, AVB reversed. Remarkably, no cases of 2° or 3° AVB were missed, suggesting mothers can recognize abnormal FHRM, reducing or precluding the need for weekly echos.

The proposed project combines the expertise of fetal cardiologist Bettina F. Cuneo, MD, initiator and PI of the FHRM program, and rheumatologist Jill P. Buyon, MD, founder/director of the largest extant registry of anti-Ro-mediated AVB, whose research on the pathogenesis supports a fetal inflammatory component associated with high-titer antibodies. Participants will be referred from 35 sites in 3 sequential Steps: 1) Screening for high titer anti-Ro60 or Ro52 centrally in Dr. Buyon's lab; 2) Surveillance by FHRM 3x daily and weekly echo; 3) Treatment of 2° AVB identified by FHRM confirmed by echo. Feasibility of FHRM supported by weekly echo of high-autoantibody-titer mothers will be leveraged to address the efficacy of expeditious (<12 h after detection) treatment of 2° AVB as well as the incidence/outcome of AV interval prolongation and extra-nodal disease.

Study Type

Interventional

Enrollment (Estimated)

1300

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Canada
    • Alberta
      • Edmonton, Alberta, Canada, AB T6G 2B7
  • United States
    • Arizona
      • Phoenix, Arizona, United States, 85016
        • Recruiting
        • Phoenix Children's Hospital/Dignity Health
        • Contact:
        • Principal Investigator:
          • Christopher Lindblade, MD
    • California
      • Los Angeles, California, United States, 90095
        • Recruiting
        • University of California - Los Angeles (UCLA)
        • Contact:
        • Contact:
        • Principal Investigator:
          • Gary Satou, MD
        • Sub-Investigator:
          • Mark Sklansky, MD
        • Sub-Investigator:
          • D Krakow, MD
      • Palo Alto, California, United States, 94305
        • Recruiting
        • Stanford University
        • Contact:
        • Principal Investigator:
          • Theresa Tacy, MD
        • Contact:
        • Sub-Investigator:
          • Michelle Kaplinski, MD
      • San Francisco, California, United States, 94143
        • Recruiting
        • University of California-San Francisco
        • Contact:
        • Principal Investigator:
          • Anita Mood-Grady, MD
    • Colorado
      • Aurora, Colorado, United States, 80204
        • Recruiting
        • University of Colorado, Denver (UCD)
        • Principal Investigator:
          • Bettina Cuneo, MD
        • Contact:
    • Connecticut
      • New Haven, Connecticut, United States, 06510
        • Recruiting
        • Yale University School of Medicine
        • Contact:
        • Principal Investigator:
          • Joshua Copel, MD
    • District of Columbia
      • Washington, District of Columbia, United States, 20010
    • Kentucky
      • Lexington, Kentucky, United States, 40536
        • Recruiting
        • University of Kentucky / Kentucky Children's Hospital
        • Contact:
        • Principal Investigator:
          • Kristopher Cumbermack, MD
      • Louisville, Kentucky, United States, 40202
        • Not yet recruiting
        • University of Louisville / Norton Children's Hospital
        • Contact:
        • Contact:
        • Principal Investigator:
          • Jyothi Matta, MBBS
        • Sub-Investigator:
          • Brian Holland, MD
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • Recruiting
        • University of Michigan / C. S. Mott Children's Hospital
        • Contact:
        • Principal Investigator:
          • Sonal Owens, MD
        • Sub-Investigator:
          • Jimmy Lu, MD
    • Minnesota
      • Minneapolis, Minnesota, United States, 55404
        • Recruiting
        • Children's Hospital of Minnesota
        • Contact:
        • Principal Investigator:
          • Lisa Howley, MD
    • New Mexico
      • Rio Rancho, New Mexico, United States, 87124
        • Recruiting
        • Perinatal Associates of New Mexico
        • Contact:
        • Principal Investigator:
          • Gary Joffe, MD
    • New York
      • New York, New York, United States, 10016
        • Recruiting
        • NYU Langone Health
        • Contact:
        • Principal Investigator:
          • Jill Buyon, MD
        • Sub-Investigator:
          • Colin Phoon, MD
      • New York, New York, United States, 10032
        • Recruiting
        • Columbia University Medical Center
        • Principal Investigator:
          • Stephanie Levasseur, MD
        • Contact:
      • New York, New York, United States, 10029
        • Recruiting
        • Mount Sinai
        • Contact:
        • Principal Investigator:
          • Erin Paul, MD
    • Ohio
      • Cleveland, Ohio, United States, 44195
        • Recruiting
        • Cleveland Clinic Lerner College of Medicine
        • Contact:
        • Principal Investigator:
          • Rukmini Komarlu, MD
      • Cleveland, Ohio, United States, 44106
        • Recruiting
        • UH Rainbow Babies / Children's Hospital
        • Contact:
        • Principal Investigator:
          • James Strainic, MD
    • Tennessee
      • Nashville, Tennessee, United States, 37232
        • Recruiting
        • Vanderbilt University Medical Center
        • Contact:
        • Principal Investigator:
          • Stacy Stratemann-Killen, MD
    • Texas
      • Houston, Texas, United States, 77030
        • Recruiting
        • Baylor College of Medicine
        • Contact:
        • Principal Investigator:
          • Tam Doan, MD
        • Sub-Investigator:
          • Shreya Sheth, MD
    • Utah
      • Salt Lake City, Utah, United States, 84102
        • Recruiting
        • University of Utah Health
        • Contact:
        • Principal Investigator:
          • Whitnee Hogan, MD
    • Vermont
      • Burlington, Vermont, United States, 05401
        • Recruiting
        • University of Vermont Children's Hospital
        • Contact:
        • Principal Investigator:
          • Caitlin Haxel, MD
    • Virginia
      • Norfolk, Virginia, United States, 23507
        • Recruiting
        • Eastern Virginia Medical School (EVMS)
        • Sub-Investigator:
          • Alfred Abuhamad, MD
        • Contact:
        • Contact:
        • Principal Investigator:
          • Elena Sinkovskaya, MD
    • Washington
      • Seattle, Washington, United States, 98105

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Provision of signed and dated informed consent form
  2. Stated willingness to comply with all study procedures and availability for the duration of the study
  3. Be <18 weeks pregnant at the time of enrollment
  4. Titer of anti-Ro 52 or 60 antibodies ≥1,000 EU
  5. Any positive titer of anti-Ro if a history of a previously affected child
  6. Ability to take oral medication and be willing to adhere to the dexamethasone and IVIG protocols.
  7. Ability to perform Doppler fetal heart rate and rhythm monitoring in the ambulatory setting,
  8. Ability to send an audiotext message by cell phone therefore the participant will be informed that they need a phone with texting capabilities. Located within 6 hours drive of the participating pediatric cardiology site
  9. Be ≥18 years of age

Exclusion Criteria:

  1. Multi-fetal pregnancy
  2. Known allergic reactions to components of IVIG, or dexamethasone or maternal IgA deficiency
  3. Fetal conduction system disease already present in the current pregnancy
  4. Any women who in the opinion of the investigator cannot understand the consent form or be able to perform thrice daily home monitoring or recognize an abnormal fetal heart rate or rhythm
  5. Women prisoners
  6. Treatment with >20 mg/prednisone q day or with any dose of fluorinated steroids at enrollment

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Mothers with Fetuses Who Have 2° AVB or AV interval > 170ms
Drug: Dexamethasone

In mother in whom 2° AVB or AV interval >170 ms has been diagnosed in the fetus:

Dexamethasone 8 mg po/day for 10 days. Then dexamethasone 4 mg po/ day through 28 weeks 6 days gestational age (GA); then 3 mg/day from 29 wks 0 days to 29 wks 6 days GA; then 2 mg/day until delivery

Drug: IVIG

In a mother in whom 2° AVB has been diagnosed in the fetus:

One dose of IVIG [1g/kg of maternal weight (max dose 70 g)] at diagnosis of 2° AVB (within 12 hours of detection by mother via home monitoring and within 6 hours of confirmation by echocardiogram). A fetal AV interval > 170 ms will not be treated with maternal IVIG, only dexamethasone.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of 2° AVB subjects with NR (1:1 AV conduction) at birth
Time Frame: up to 25 weeks post-enrollment
The presence of NR (normal rhythm) will be determined by electrocardiogram (ECG)
up to 25 weeks post-enrollment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of 2° AVB subjects who maintain NR at age 1 year.
Time Frame: 1 year post-birth
The presence of NR will be determined by ECG
1 year post-birth
Percentage of AV interval > 170 msec subjects with NR at birth
Time Frame: At birth
AV intervals will be determined by EKG
At birth
Incidences of isolated extra-nodal cardiac disease
Time Frame: up to 1 year post-birth
Extra-nodal cardiac disease includes: Endocardial fibroelastosis, dilated cardiomyopathy, and AV valve insufficiency. Isolated exta-nodal cardiac disease will be determined by echocardiogram.
up to 1 year post-birth

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

NYU Langone Health

Investigators

  • Principal Investigator: Jill Buyon, MD, NYU Langone Health
  • Principal Investigator: Bettina Cuneo, MD, University of Colorado, Denver

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 1, 2020

Primary Completion (Estimated)

August 1, 2025

Study Completion (Estimated)

October 31, 2026

Study Registration Dates

First Submitted

July 14, 2020

First Submitted That Met QC Criteria

July 14, 2020

First Posted (Actual)

July 16, 2020

Study Record Updates

Last Update Posted (Actual)

July 19, 2023

Last Update Submitted That Met QC Criteria

July 18, 2023

Last Verified

July 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 20-00363

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices) will be shared upon reasonable request.

IPD Sharing Time Frame

Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.

IPD Sharing Access Criteria

The investigator who proposes to use the data will have access to the data upon reasonable request and when a stated purpose and approval by a committee is provided. Requests should be directed to Jill.Buyon@nyulangone.org. To gain access, data requestors will need to sign a data access agreement.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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