Surveillance and Treatment to Prevent Fetal Atrioventricular Block Likely to Occur Quickly (STOP BLOQ)
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|ClinicalTrials.gov Identifier: NCT04474223|
Recruitment Status : Recruiting
First Posted : July 16, 2020
Last Update Posted : September 18, 2020
|Condition or disease||Intervention/treatment||Phase|
|AVB - Atrioventricular Block Fetal AVB||Drug: Dexamethasone Drug: IVIG||Phase 3|
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 (Clinical Trial)|
|Estimated Enrollment :||1300 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Surveillance and Treatment to Prevent Fetal Atrioventricular Block Likely to Occur Quickly (STOP BLOQ)|
|Actual Study Start Date :||August 1, 2020|
|Estimated Primary Completion Date :||August 1, 2025|
|Estimated Study Completion Date :||January 1, 2026|
|Experimental: Mothers with Fetuses Who Have 2° AVB or AV interval > 170ms||
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
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.
- 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)
- 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
- Percentage of AV interval > 170 msec subjects with NR at birth [ Time Frame: At birth ]AV intervals will be determined by EKG
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04474223
|Contact: Rebecca Cohen||646-501-0578||Rebecca.Cohen@nyulangone.org|
|Contact: Jill Buyon, MD||212-263-0756||Jill.Buyon@nyulangone.org,|
|Principal Investigator:||Jill Buyon, MD||NYU Langone Health|
|Principal Investigator:||Bettina Cuneo, MD||University of Colorado, Denver|