Preventive Approach to Congenital Heart Block With Hydroxychloroquine (PATCH)

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2013 by New York University School of Medicine
Sponsor:
Information provided by (Responsible Party):
Jill P. Buyon, New York University School of Medicine
ClinicalTrials.gov Identifier:
NCT01379573
First received: June 16, 2011
Last updated: June 7, 2013
Last verified: June 2013
  Purpose

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 plans to enroll 19 patients in the first year. Patients can already be on hydroxychloroquine or will be started as soon as pregnancy is confirmed. The hope is that less than 3 cases of heart block will occur. 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.


Condition Intervention Phase
Congenital Heart Block
Neonatal Lupus
Autoantibody-Associated Heart Block
Drug: Hydroxychloroquine
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Preventive Approach to Congenital Heart Block With Hydroxychloroquine

Resource links provided by NLM:


Further study details as provided by New York University School of Medicine:

Primary Outcome Measures:
  • Recurrence of advanced heart block [ Time Frame: 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) ] [ Designated as safety issue: No ]
    Echocardiogram reveals 2nd or 3rd degree AV block


Secondary Outcome Measures:
  • Prolonged PR interval (>150msec) [ Time Frame: 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) ] [ Designated as safety issue: No ]
    EKG at birth must confirm 1st degree AV block. It is also possible that a fetus developing 1st degree block on study medication might have developed more advanced block in the absence of study medication.

  • Any sign of myocardial injury, without change in cardiac rate or rhythm [ Time Frame: 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) ] [ Designated as safety issue: No ]
    a) shortening fraction <28% = 2 SD below normal mean or qualitatively reduced systolic function; b) cardio-thoracic ratio >0.33; c) hydropic changes; d) moderate/severe tricuspid regurgitation.

  • Echocardiographic densities consistent with EFE confirmed postnatally [ Time Frame: 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) ] [ Designated as safety issue: No ]
    (see title)

  • Fetal death not related to cardiac dysfunction [ Time Frame: Up to 9 months ] [ Designated as safety issue: No ]
    An autopsy with full evaluation of the heart will be encouraged but cannot be mandated. If AV block or evidence of a cardiomyopathy can be "proven," then these will provide the basis for final categorization. If not possible, the death will not be considered a recurrence rate but will be reported.

  • NL rash [ Time Frame: Up to 15 months (at birth - 9 months, and 6 months thereafter) ] [ Designated as safety issue: Yes ]
  • Prematurity [ Time Frame: At birth (approximately 9 months) ] [ Designated as safety issue: Yes ]
    (gestational age <37 weeks at birth)

  • Birth weight <10% in the context of gestational age [ Time Frame: At birth (approximately 9 months) ] [ Designated as safety issue: Yes ]
  • Abnormal fluid collection [ Time Frame: At birth (approximately 9 months) ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 19
Study Start Date: January 2011
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Hydroxychloroquine
    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.
    Other Name: Plaquenil
Detailed Description:

One of the strongest clinical associations with autoantibodies directed to components of the Ro/La ribonucleoprotein complex is the development of congenital heart block (CHB) in an offspring, an alarming prospect facing 2% of primigravid mothers with these reactivities. The risk is 10-fold higher in women who have had a previously affected child. Despite the attempt of large multicenter studies to forestall disease by serial in utero monitoring, irreversible block and extensive myocardial injury have been documented within 7 days of a normal rhythm and PR interval. CHB is associated with a substantial mortality and morbidity. Two recent prospective studies (20 mothers from U.S. and 15 from Europe) utilizing an identical protocol of IVIG at replacement doses demonstrated 1) this intervention does not prevent the recurrence of CHB 2) the recurrence rate of 17-18% is robust 3) recruitment of patients is feasible. During the time period of the IVIG trials, basic science exploring the pathogenesis of disease supported the notion that Toll Like Receptor (TLR) signaling following ligation of ssRNA (hY3) complexed to the Ro protein contributes to fibrosis. This observation led to in vitro studies addressing inhibition of endosomal acidification by chloroquine and subsequent translation to patients by evaluating the use of hydroxychloroquine (HCQ) in an extensive retrospective chart review. The combined data suggest efficacy of HCQ. Accordingly, the goal of this one year study is to: To determine whether hydroxychloroquine use during pregnancy prevents CHB in a high risk population. The trial is open-label and employs the Simon's 2-stage optimal design to allow for early stopping due to absence of treatment efficacy. The first stage requires 19 subjects which are expected to be enrolled in one year. Despite the rarity of disease and the requirement of a previous CHB child, based on the US Research Registry for Neonatal Lupus (our extensive domestic database, which includes at least 9 families from Minnesota) and data from the U.K., this proposal is feasible. If 3 or more mothers have a child with 2nd or 3rd degree CHB, the study is terminated after the first stage. If this does not occur, funds will be sought to enroll an additional 35 mothers in the second stage for a total of 54 subjects. Treatment will be considered efficacious if fewer than 6 mothers of 54 have a child with advanced CHB. With this design, the study has 90% power to conclude that hydroxychloroquine is preventive if the true recurrence rate with the treatment is 5%. In addition, the probability of rejecting the treatment for further study is 95% if the true recurrence rate is 18%. Serial echocardiograms (monitor PR interval) and blood drawing (IFNƒÑƒnsignatures, antibody titers) will be included in the protocol. The results of this study are expected to become an integral part of the counseling of women with anti-SSA/Ro-SSB/La antibodies who are considering pregnancy.

  Eligibility

Ages Eligible for Study:   18 Years to 45 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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). Dr. Khamashta will likewise verify Ab in his laboratory.
  2. Mothers must have a previous child with cardiac NL, defined herein as: the presence of heart block (1st, 2nd, or 3rd degree) documented by electrocardiogram (EKG), echocardiogram, pacemaker, or statement in the medical record, and/or; presence of cardiac injury, which specifically includes autopsy evidence of a mononuclear infiltrate in the endocardium, myocardium, and pericardium and/or EFE on echocardiogram always associated with cardiac dysfunction. In PITCH, we included women with a prior child with rash; however, recent data generated from the RRNL suggest that recurrence of CHB following rash is 11%, not 18% [34]. Thus, inclusion of previous rash could lead to a falsely lowered recurrence rate, and will therefore be excluded.
  3. Intrauterine pregnancy ≤10 weeks.
  4. Mother may be taking ≤20 mg prednisone because, in our experience, CHB has developed in the presence of this dose.
  5. 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.
  6. 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.

Exclusion Criteria:

  1. Mother does not have Ab to Ro or La.
  2. 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.
  3. Mother is taking > 20 mg prednisone/day. Although unlikely to be preventative, higher doses will constitute an exclusion. The final point of intense discussion centered around whether another exclusion should be the use of HCQ in the first pregnancy in which CHB occurred. While one could argue that in these mothers HCQ was not effective and perhaps will not be again, this assumption remains speculative and thus prior absence of efficacy of HCQ will not constitute an exclusion criteria.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01379573

Contacts
Contact: Jill P Buyon, MD 212-263-0746 jill.buyon@nyumc.org
Contact: Zoey Smith, BA 212-263-0743 zoey.smith@nyumc.org

Locations
United States, New York
New York University School of Medicine Recruiting
New York, New York, United States, 10016
Contact: Jill P Buyon, MD    212-263-0746    jill.buyon@nyumc.org   
Contact: Zoey Smith, BA    212-263-0743    zoey.smith@nyumc.org   
Sponsors and Collaborators
New York University School of Medicine
Investigators
Principal Investigator: Jill P Buyon, MD New York University School of Medicine
  More Information

Additional Information:
No publications provided

Responsible Party: Jill P. Buyon, M.D., New York University School of Medicine
ClinicalTrials.gov Identifier: NCT01379573     History of Changes
Other Study ID Numbers: 11-00369
Study First Received: June 16, 2011
Last Updated: June 7, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by New York University School of Medicine:
Sjogren's syndrome
hydroxychloroquine
Plaquenil
congenital heart block
neonatal lupus
systemic lupus erythematosus
autoantibodies
SSA/Ro
SSB/La
autoimmunity
pregnancy
immunoglobulin

Additional relevant MeSH terms:
Heart Block
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Hydroxychloroquine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents

ClinicalTrials.gov processed this record on September 22, 2014