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

NCT ID: NCT04474223

Last Updated: 2025-04-09

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 1300 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-08-01
• Study Completion Date: 2029-06-30

Brief Summary

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.

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.

Conditions

AVB - Atrioventricular Block; Fetal AVB

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Mothers with Fetuses Who Have 2° AVB or AV interval > 170ms

Group Type: EXPERIMENTAL

Dexamethasone

Intervention Type: DRUG

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

IVIG

Intervention Type: DRUG

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.

Interventions

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

Intervention Type: 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.

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

NYU Langone Health

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jill Buyon, MD

Role: PRINCIPAL_INVESTIGATOR

NYU Langone Health

Bettina Cuneo, MD

Role: PRINCIPAL_INVESTIGATOR

University of Colorado, Denver

Locations

Phoenix Children's Hospital/Dignity Health

Phoenix, Arizona, United States

Site Status: RECRUITING

University of California - Los Angeles (UCLA)

Los Angeles, California, United States

Site Status: RECRUITING

Stanford University

Palo Alto, California, United States

Site Status: RECRUITING

University of California-San Francisco

San Francisco, California, United States

Site Status: RECRUITING

University of Colorado, Denver (UCD)

Aurora, Colorado, United States

Site Status: RECRUITING

Yale University School of Medicine

New Haven, Connecticut, United States

Site Status: RECRUITING

Children's National Medical Center/George Washington University

Washington D.C., District of Columbia, United States

Site Status: RECRUITING

University of Kentucky / Kentucky Children's Hospital

Lexington, Kentucky, United States

Site Status: RECRUITING

University of Louisville / Norton Children's Hospital

Louisville, Kentucky, United States

Site Status: NOT_YET_RECRUITING

University of Michigan / C. S. Mott Children's Hospital

Ann Arbor, Michigan, United States

Site Status: RECRUITING

Children's Hospital of Minnesota

Minneapolis, Minnesota, United States

Site Status: RECRUITING

Perinatal Associates of New Mexico

Rio Rancho, New Mexico, United States

Site Status: RECRUITING

NYU Langone Health

New York, New York, United States

Site Status: RECRUITING

Mount Sinai

New York, New York, United States

Site Status: RECRUITING

Columbia University Medical Center

New York, New York, United States

Site Status: RECRUITING

UH Rainbow Babies / Children's Hospital

Cleveland, Ohio, United States

Site Status: RECRUITING

Cleveland Clinic Lerner College of Medicine

Cleveland, Ohio, United States

Site Status: RECRUITING

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Site Status: RECRUITING

Baylor College of Medicine

Houston, Texas, United States

Site Status: RECRUITING

University of Utah Health

Salt Lake City, Utah, United States

Site Status: RECRUITING

University of Vermont Children's Hospital

Burlington, Vermont, United States

Site Status: RECRUITING

Eastern Virginia Medical School (EVMS)

Norfolk, Virginia, United States

Site Status: RECRUITING

Seattle Children's Hospital

Seattle, Washington, United States

Site Status: NOT_YET_RECRUITING

Stollery Children's Hospital

Edmonton, Alberta, Canada

Site Status: NOT_YET_RECRUITING

Countries

United States; Canada

Central Contacts

Mala Masson

Role: CONTACT

mala.masson@nyulangone.org

212-263-0372

Jill Buyon, MD

Role: CONTACT

Jill.Buyon@nyulangone.org,

212-263-0756

Facility Contacts

Christopher Lindblade, MD

Role: primary

clindblade@phoenixchildrens.com

Gary Satou, MD

Role: primary

GSatou@mednet.ucla.edu

Mark Sklansky, MD

Role: backup

MSklansky@mednet.ucla.edu

Theresa Tacy, MD

Role: primary

tatacy@stanford.edu

Michelle Kaplinski, MD

Role: backup

mkaplinsk@stanford.edu

Anita Mood-Grady, MD

Role: primary

Anita.Grady@ucsf.edu

Bettina Cuneo, MD

Role: primary

Bettina.Cuneo@childrenscolorado.org

720-777-1030

Joshua Copel, MD

Role: primary

joshua.copel@yale.edu

Anita Krishnan, MD

Role: primary

AKrishna@childrensnational.org

Mary Donofrio, MD

Role: backup

MDonofri@childrensnational.org

Kristopher Cumbermack, MD

Role: primary

KCumbermack@uky.edu

Jyothi Matta, MBBS

Role: primary

Jyothi.Matta@louisville.edu

Brian Holland, MD

Role: backup

brian.holland@louisville.edu

Sonal Owens, MD

Role: primary

sthakkar@med.umich.edu

Lisa Howley, MD

Role: primary

lhowley@chc-pa.org

Gary Joffe, MD

Role: primary

gjoffe@panm.com

Colin Phoon, MD

Role: primary

Colin.Phoon@nyulangone.org

Erin Paul, MD

Role: primary

Erin.Paul@mssm.edu

Stephanie Levasseur, MD

Role: primary

sl2363@cumc.columbia.edu

James Strainic, MD

Role: primary

James.Strainic@UHhospitals.org

Rukmini Komarlu, MD

Role: primary

komarlr@ccf.org

Stacy Stratemann-Killen, MD

Role: primary

stacy.stratemann@vumc.org

Tam Doan, MD

Role: primary

tam.doan@bcm.edu

Whitnee Hogan, MD

Role: primary

Whitnee.Hogan@hsc.utah.edu

Caitlin Haxel, MD

Role: primary

caitlin.haxel@uvmhealth.org

Elena Sinkovskaya, MD

Role: primary

sinkove@evms.edu

Alfred Abuhamad, MD

Role: backup

abuhamaz@evms.edu

Bhawna Arya, MD

Role: primary

Bhawna.Arya@seattlechildrens.org

Lisa Hornberger, MD

Role: primary

Lisa.Hornberger@albertahealthservices.ca

Other Identifiers

20-00363

Identifier Type: -

Identifier Source: org_study_id