Preventive Approach to Congenital Heart Block With Hydroxychloroquine

NCT01379573 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 11-00369
• Study Type: interventional
• Target: 74
• Locations: 1 country
• Sites: 1

Brief Summary

Women with antibodies to proteins called SSA/Ro and or SSB/La face a 2% chance of having a child with a life threatening heart condition regardless of whether they have very active lupus, are in remission, or have only vague symptoms. This heart problem is referred to as congenital heart block (the most serious being third degree complete block) and represents damage thought to be caused by these autoantibodies. The heart beats abnormally slowly and almost all children require permanent pacemakers before the age of 20. Importantly, women who have had one child with heart block have a ten-fold higher risk of having another child with the same heart condition. Unfortunately, even close monitoring by special techniques during pregnancy does not reverse complete heart block once it is observed. Thus, treatments aimed at prevention are critical. This study will evaluate for the first time whether hydroxychloroquine, a drug used by many patients with SLE, prevents the development of this heart condition. Data from laboratory experiments suggests that this drug, which crosses the placenta, may decrease the inflammation initiated by the passage of anti-Ro antibodies to the fetus. The study uses a Simon's 2-Stage design, and plans to enroll 19 patients in Stage 1 and 35 patients in Stage 2 if Stage 1 is successful. Patients can already be on hydroxychloroquine or will be started as soon as pregnancy is confirmed. The hope is that fewer than 3 cases of heart block will occur in Stage 1, and fewer than 6 cases will occur out of all 54 patients if Stage 2 is reached. The results of this study are expected to become an integral part of the counseling of women with anti-Ro/La antibodies who are considering pregnancy.

Conditions

Congenital Heart Block; Neonatal Lupus; Autoantibody-Associated Heart Block

Keywords

hydroxychloroquine; Plaquenil; congenital heart block; neonatal lupus; systemic lupus erythematosus; Sjogren's syndrome; autoantibodies; SSA/Ro; SSB/La; autoimmunity; pregnancy; immunoglobulin

Outcome Measures

Primary Outcomes (1)

• Recurrence of Advanced Heart Block

  Echocardiogram reveals 2nd or 3rd degree AV block

  After enrollment at 16-18 weeks gestation, then weekly until 26 weeks, biweekly to 34 weeks, at birth (approximately 9 months), and at one year follow up (approximately 21 months from enrollment)

Secondary Outcomes (8)

• Prolonged PR Interval (>150msec)

  After enrollment at 16-18 weeks gestation, then weekly until 26 weeks, biweekly to 34 weeks, at birth (approximately 9 months), and at one year follow up (approximately 21 months from enrollment)

• Any Sign of Myocardial Injury, Without Change in Cardiac Rate or Rhythm

  After enrollment at 16-18 weeks gestation, then weekly until 26 weeks, biweekly to 34 weeks, at birth (approximately 9 months), and at one year follow up (approximately 21 months from enrollment)

• Echocardiographic Densities Consistent With EFE Confirmed Postnatally

  After enrollment at 16-18 weeks gestation, then weekly until 26 weeks, biweekly to 34 weeks, at birth (approximately 9 months), and at one year follow up (approximately 21 months from enrollment)

• Fetal Death Not Related to Cardiac Dysfunction

  Up to 9 months

• Cutaneous Neonatal Lupus

  Up to 15 months (at birth - 9 months, and 6 months thereafter)

Study Arms (1)

Pregnant women with previous child with cardiac neonatal lupus

EXPERIMENTAL

400 mg/day Hydroxychloroquine

Drug: Hydroxychloroquine

Interventions

Hydroxychloroquine DRUG

Nineteen women meeting eligibility criteria will receive 400mg per day of HCQ beginning as soon as pregnancy is established and informed consent obtained. Mothers already on HCQ will remain on 400mg, or escalate to 400mg if on 200mg. Hydroxychloroquine is taken in 200mg pill form - 400mg = 2 200mg pills.

Also known as: Plaquenil

Pregnant women with previous child with cardiac neonatal lupus

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Mothers must have anti-Ro and/or anti-La Ab documented in the NYU immunology laboratory (CLIA-approved), which utilizes an ELISA as well as reactivity on ELISA to at least one of three recombinant antigens (48La, 52Ro, 60Ro, JB laboratory).
• Intrauterine pregnancy ≤10 weeks.
• Mother may be taking ≤20 mg prednisone because, in our experience, CHB has developed in the presence of this dose.
• Mother may be asymptomatic, or have a rheumatic disease such as SLE or SS. Maternal health status has not been considered an influence on the development of CHB.
• Mother may or may not already be taking HCQ. This latter point was discussed with Dr. Nathalie Costedoat-Chalumeau, who has published extensively on measurement of HCQ. While it might be optimal for the mothers anticipating enrollment in the study to all have been on HCQ prior to conception, this is impractical. Some may never achieve pregnancy and not want to take HCQ unless they conceive (especially those asymptomatic). On the other hand, women with SLE are likely to already be on HCQ and it would limit enrollment to exclude these patients if all must initiate HCQ only at enrollment in the first trimester. Although the accepted dogma is that HCQ requires several months for maximal efficacy in treating rheumatic disease, it is unknown whether this would apply to transplacental passage or fetal levels (which are impossible to measure). Dr. Costedoat-Chalumeau suggests that HCQ is probably a three compartment model which includes the circulation, tissues and cells. In the circulation, the half life is approximately 7 days and in the tissues, it is 40 days. In Dr. Costedoat-Chalumeau's experience, steady state blood levels of HCQ are achieved in 4-6 weeks. Thus, dosing the mother no later than 10 weeks gestation should provide sufficient fetal exposure before the vulnerable period of CHB which is generally accepted to span 18-24 wks. Furthermore, the placenta has to be formed for HCQ to gain access to the fetus and it may be effective quickly for the biology we are considering.

You may not qualify if:

• Mother does not have Ab to Ro or La.
• Identification of any of the following structural lesions considered causal for CHB, i.e., those that could account for block because of fibrous disruption between the atrium and AV node or due to absence of the penetrating bundles of the AV node:
• atrioventricular septal defects;
• b) single ventricle
• c) developmental tricuspid valve disease;
• d) L-transposition of the great arteries;
• e) heterotaxia.

Sponsors & Collaborators

• NYU Langone Health: lead

Study Sites (1)

New York University School of Medicine

New York, New York, 10016, United States

Location

Related Publications (2)

• Friedman DM, Kim M, Costedoat-Chalumeau N, Clancy R, Copel J, Phoon CK, Cuneo BF, Cohen R, Masson M, Wainwright BJ, Zahr N, Saxena A, Izmirly PM, Buyon JP. Electrocardiographic QT Intervals in Infants Exposed to Hydroxychloroquine Throughout Gestation. Circ Arrhythm Electrophysiol. 2020 Oct;13(10):e008686. doi: 10.1161/CIRCEP.120.008686. Epub 2020 Sep 9.

  PMID: 32907357 DERIVED

• Izmirly P, Kim M, Friedman DM, Costedoat-Chalumeau N, Clancy R, Copel JA, Phoon CKL, Cuneo BF, Cohen RE, Robins K, Masson M, Wainwright BJ, Zahr N, Saxena A, Buyon JP. Hydroxychloroquine to Prevent Recurrent Congenital Heart Block in Fetuses of Anti-SSA/Ro-Positive Mothers. J Am Coll Cardiol. 2020 Jul 21;76(3):292-302. doi: 10.1016/j.jacc.2020.05.045.

  PMID: 32674792 DERIVED

MeSH Terms

Conditions

Congenital heart block; Neonatal Systemic lupus erythematosus; Lupus Erythematosus, Systemic; Sjogren's Syndrome; Autoimmune Diseases

Interventions

Hydroxychloroquine

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Immune System Diseases; Arthritis, Rheumatoid; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Xerostomia; Salivary Gland Diseases; Mouth Diseases; Stomatognathic Diseases; Dry Eye Syndromes; Lacrimal Apparatus Diseases; Eye Diseases

Intervention Hierarchy (Ancestors)

Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Jill Buyon
• Organization: NYU Langone Health

Jill.Buyon@nyulangone.org

+1 212 263 0746

Study Officials

• Jill P Buyon, MD

  NYU Langone Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 16, 2011
• First Posted: June 23, 2011
• Study Start: January 1, 2011
• Primary Completion: July 16, 2020
• Study Completion: July 16, 2020
• Last Updated: February 25, 2021
• Results First Posted: March 16, 2020

Record last verified: 2021-02

Locations

US (1)