Clinical trial NCT04474223: Surveillance and Treatment to Prevent Fetal Atrioventricular Block Likely to Occur Quickly (STOP BLOQ)
Official title: Surveillance and Treatment to Prevent Fetal Atrioventricular Block Likely to Occur Quickly (STOP BLOQ)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: AVB - Atrioventricular Block
Fetal AVB
Lead sponsor: NYU Langone Health
Sponsor class: OTHER
First posted: 2020-07-16
Enrollment: 1300
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Percentage of 2° AVB subjects with NR (1:1 AV conduction) at birth
timeFrame: up to 25 weeks post-enrollment
Secondary outcomes:
measure: Percentage of 2° AVB subjects who maintain NR at age 1 year.
timeFrame: 1 year post-birth
measure: Percentage of AV interval > 170 msec subjects with NR at birth
timeFrame: At birth
measure: Incidences of isolated extra-nodal cardiac disease
timeFrame: up to 1 year post-birth
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Children's Hospital/Dignity Health
state: Arizona
city: Los Angeles
country: United States
facility: University of California - Los Angeles (UCLA)
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: San Francisco
country: United States
facility: University of California-San Francisco
state: California
city: Aurora
country: United States
facility: University of Colorado, Denver (UCD)
state: Colorado
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Washington
country: United States
facility: Children's National Medical Center/George Washington University
state: District of Columbia
city: Lexington
country: United States
facility: University of Kentucky / Kentucky Children's Hospital
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville / Norton Children's Hospital
state: Kentucky
city: Ann Arbor
country: United States
facility: University of Michigan / C. S. Mott Children's Hospital
state: Michigan
city: Minneapolis
country: United States
facility: Children's Hospital of Minnesota
state: Minnesota
city: Rio Rancho
country: United States
facility: Perinatal Associates of New Mexico
state: New Mexico
city: New York
country: United States
facility: NYU Langone Health
state: New York
city: New York
country: United States
facility: Mount Sinai
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Cleveland
country: United States
facility: UH Rainbow Babies / Children's Hospital
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Lerner College of Medicine
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Health
state: Utah
city: Burlington
country: United States
facility: University of Vermont Children's Hospital
state: Vermont
city: Norfolk
country: United States
facility: Eastern Virginia Medical School (EVMS)
state: Virginia
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Edmonton
country: Canada
facility: Stollery Children's Hospital
state: Alberta
Study officials:
affiliation: NYU Langone Health
name: Jill Buyon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Colorado, Denver
name: Bettina Cuneo, MD
role: PRINCIPAL_INVESTIGATOR
References: