Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04474223
Recruitment Status : Recruiting
First Posted : July 16, 2020
Last Update Posted : September 18, 2020
Sponsor:
Information provided by (Responsible Party):
NYU Langone Health

Tracking Information
First Submitted Date  ICMJE July 14, 2020
First Posted Date  ICMJE July 16, 2020
Last Update Posted Date September 18, 2020
Actual Study Start Date  ICMJE August 1, 2020
Estimated Primary Completion Date August 1, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 14, 2020)
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)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 14, 2020)
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Surveillance and Treatment to Prevent Fetal Atrioventricular Block Likely to Occur Quickly (STOP BLOQ)
Official Title  ICMJE Surveillance and Treatment to Prevent Fetal Atrioventricular Block Likely to Occur Quickly (STOP BLOQ)
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • AVB - Atrioventricular Block
  • Fetal AVB
Intervention  ICMJE
  • 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

  • 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.

Study Arms  ICMJE Experimental: Mothers with Fetuses Who Have 2° AVB or AV interval > 170ms
Interventions:
  • Drug: Dexamethasone
  • Drug: IVIG
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 14, 2020)
1300
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 1, 2026
Estimated Primary Completion Date August 1, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Gender Based Eligibility: Yes
Gender Eligibility Description: Must be <18 weeks pregnant at the time of enrollment
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Rebecca Cohen 646-501-0578 Rebecca.Cohen@nyulangone.org
Contact: Jill Buyon, MD 212-263-0756 Jill.Buyon@nyulangone.org,
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04474223
Other Study ID Numbers  ICMJE 20-00363
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices) will be shared upon reasonable request.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Time Frame: Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.
Access Criteria: The investigator who proposes to use the data will have access to the data upon reasonable request and when a stated purpose and approval by a committee is provided. Requests should be directed to Jill.Buyon@nyulangone.org. To gain access, data requestors will need to sign a data access agreement.
Responsible Party NYU Langone Health
Study Sponsor  ICMJE NYU Langone Health
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jill Buyon, MD NYU Langone Health
Principal Investigator: Bettina Cuneo, MD University of Colorado, Denver
PRS Account NYU Langone Health
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP