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

AVB - Atrioventricular Block Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04474223
• Other study ID #: 20-00363
• Status: Recruiting
• Phase: Phase 3
• Start date: August 1, 2020
• Est. completion date: October 31, 2026

Study information

• Verified date: May 2024
• Source: NYU Langone Health
• Contact: Mala Masson
• Phone: 212-263-0372
• Email: mala.masson[@]nyulangone.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1300
• Est. completion date: October 31, 2026
• Est. primary completion date: August 1, 2026
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Atrioventricular Block
• AVB - Atrioventricular Block
• Fetal AVB

Intervention

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
• 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.

Locations

Country	Name	City	State
Canada	Stollery Children's Hospital	Edmonton	Alberta
United States	University of Michigan / C. S. Mott Children's Hospital	Ann Arbor	Michigan
United States	University of Colorado, Denver (UCD)	Aurora	Colorado
United States	University of Vermont Children's Hospital	Burlington	Vermont
United States	Cleveland Clinic Lerner College of Medicine	Cleveland	Ohio
United States	UH Rainbow Babies / Children's Hospital	Cleveland	Ohio
United States	Baylor College of Medicine	Houston	Texas
United States	University of Kentucky / Kentucky Children's Hospital	Lexington	Kentucky
United States	University of California - Los Angeles (UCLA)	Los Angeles	California
United States	University of Louisville / Norton Children's Hospital	Louisville	Kentucky
United States	Children's Hospital of Minnesota	Minneapolis	Minnesota
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Columbia University Medical Center	New York	New York
United States	Mount Sinai	New York	New York
United States	NYU Langone Health	New York	New York
United States	Eastern Virginia Medical School (EVMS)	Norfolk	Virginia
United States	Stanford University	Palo Alto	California
United States	Phoenix Children's Hospital/Dignity Health	Phoenix	Arizona
United States	Perinatal Associates of New Mexico	Rio Rancho	New Mexico
United States	University of Utah Health	Salt Lake City	Utah
United States	University of California-San Francisco	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Children's National Medical Center/George Washington University	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
NYU Langone Health

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of 2° AVB subjects with NR (1:1 AV conduction) at birth	The presence of NR (normal rhythm) will be determined by electrocardiogram (ECG)	up to 25 weeks post-enrollment
Secondary	Percentage of 2° AVB subjects who maintain NR at age 1 year.	The presence of NR will be determined by ECG	1 year post-birth
Secondary	Percentage of AV interval > 170 msec subjects with NR at birth	AV intervals will be determined by EKG	At birth
Secondary	Incidences of isolated extra-nodal cardiac disease	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