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

Phase 3

Recruiting

• Conditions: AVB - Atrioventricular Block; Fetal AVB
• Interventions: Drug: Dexamethasone; Drug: IVIG

• Registration Number: NCT04474223
• Lead Sponsor: NYU Langone Health

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2020-07-14
• Study First Submitted QC: 2020-07-14
• Study First Posted: 2020-07-16
• Study Start: 2020-08-01
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-17
• Last Update Posted: 2024-05-20
• Primary Completion: 2026-08-01
• Study Completion: 2026-10-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Female
• Target Recruitment: 1300

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Mothers with Fetuses Who Have 2° AVB or AV interval > 170ms	IVIG	-
Mothers with Fetuses Who Have 2° AVB or AV interval > 170ms	Dexamethasone	-

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Percentage of 2° AVB subjects who maintain NR at age 1 year.	1 year post-birth	The presence of NR will be determined by ECG
Incidences of isolated extra-nodal cardiac disease	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.
Percentage of AV interval > 170 msec subjects with NR at birth	At birth	AV intervals will be determined by EKG

Trial Locations

Locations (24)

University of California - Los Angeles (UCLA); 🇺🇸 Los Angeles, California, United States

Cleveland Clinic Lerner College of Medicine; 🇺🇸 Cleveland, Ohio, United States

UH Rainbow Babies / Children's Hospital; 🇺🇸 Cleveland, Ohio, United States

Children's Hospital of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

Baylor College of Medicine; 🇺🇸 Houston, Texas, United States

Stanford University; 🇺🇸 Palo Alto, California, United States

University of California-San Francisco; 🇺🇸 San Francisco, California, United States

Perinatal Associates of New Mexico; 🇺🇸 Rio Rancho, New Mexico, United States

NYU Langone Health; 🇺🇸 New York, New York, United States

Mount Sinai; 🇺🇸 New York, New York, United States

Columbia University Medical Center; 🇺🇸 New York, New York, United States

Eastern Virginia Medical School (EVMS); 🇺🇸 Norfolk, Virginia, United States

Seattle Children's Hospital; 🇺🇸 Seattle, Washington, United States

University of Colorado, Denver (UCD); 🇺🇸 Aurora, Colorado, United States

University of Utah Health; 🇺🇸 Salt Lake City, Utah, United States

University of Vermont Children's Hospital; 🇺🇸 Burlington, Vermont, United States

Children's National Medical Center/George Washington University; 🇺🇸 Washington, District of Columbia, United States

Phoenix Children's Hospital/Dignity Health; 🇺🇸 Phoenix, Arizona, United States

University of Louisville / Norton Children's Hospital; 🇺🇸 Louisville, Kentucky, United States

University of Michigan / C. S. Mott Children's Hospital; 🇺🇸 Ann Arbor, Michigan, United States

Yale University School of Medicine; 🇺🇸 New Haven, Connecticut, United States

University of Kentucky / Kentucky Children's Hospital; 🇺🇸 Lexington, Kentucky, United States

Stollery Children's Hospital; 🇨🇦 Edmonton, Alberta, Canada