PATCH: Preventive Approach to Congenital Heart Block With Hydroxychloroquine

Sponsor
NYU Langone Health (Other)
Overall Status
Completed
CT.gov ID
NCT01379573
Collaborator
(none)
74
1
1
114.5
0.6

Study Details

Study Description

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.

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 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. Despite the rarity of disease and the requirement of a previous CHB child, based on the US Research Registry for Neonatal Lupus, 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.

Study Design

Study Type:
Interventional
Actual Enrollment :
74 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Prevention
Official Title:
Preventive Approach to Congenital Heart Block With Hydroxychloroquine
Actual Study Start Date :
Jan 1, 2011
Actual Primary Completion Date :
Jul 16, 2020
Actual Study Completion Date :
Jul 16, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Pregnant women with previous child with cardiac neonatal lupus

400 mg/day Hydroxychloroquine

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 Names:
  • Plaquenil
  • Outcome Measures

    Primary Outcome Measures

    1. Recurrence of Advanced Heart 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)]

      Echocardiogram reveals 2nd or 3rd degree AV block

    Secondary Outcome Measures

    1. 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)]

      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.

    2. 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)]

      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.

    3. 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)]

      (see title)

    4. Fetal Death Not Related to Cardiac Dysfunction [Up to 9 months]

      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.

    5. Cutaneous Neonatal Lupus [Up to 15 months (at birth - 9 months, and 6 months thereafter)]

    6. Prematurity [At birth (approximately 9 months)]

      (gestational age <37 weeks at birth)

    7. Birth Weight <10% in the Context of Gestational Age [At birth (approximately 9 months)]

    8. Abnormal Fluid Collection [At birth (approximately 9 months)]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 45 Years
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    No
    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).

    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;

      1. single ventricle
      1. developmental tricuspid valve disease;
      1. L-transposition of the great arteries;
      1. heterotaxia.
    1. Mother is taking any glucocorticoids. Although unlikely to be preventative, the use of steroids may confound the interpretation of results. 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

    Locations

    Site City State Country Postal Code
    1 New York University School of Medicine New York New York United States 10016

    Sponsors and Collaborators

    • NYU Langone Health

    Investigators

    • Principal Investigator: Jill P Buyon, MD, NYU Langone Health

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    NYU Langone Health
    ClinicalTrials.gov Identifier:
    NCT01379573
    Other Study ID Numbers:
    • 11-00369
    First Posted:
    Jun 23, 2011
    Last Update Posted:
    Feb 25, 2021
    Last Verified:
    Feb 1, 2021
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by NYU Langone Health
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Pregnant Women With Previous Child With Cardiac Neonatal Lupus
    Arm/Group Description 400 mg/day Hydroxychloroquine Hydroxychloroquine: 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.
    Period Title: Overall Study
    STARTED 74
    COMPLETED 63
    NOT COMPLETED 11

    Baseline Characteristics

    Arm/Group Title Pregnant Women With Previous Child With Cardiac Neonatal Lupus
    Arm/Group Description 400 mg/day Hydroxychloroquine 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.
    Overall Participants 63
    Age (years) [Mean (Full Range) ]
    Mean (Full Range) [years]
    32.7
    Sex: Female, Male (Count of Participants)
    Female
    63
    100%
    Male
    0
    0%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    3
    4.8%
    Not Hispanic or Latino
    60
    95.2%
    Unknown or Not Reported
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    1
    1.6%
    Asian
    8
    12.7%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    6
    9.5%
    White
    45
    71.4%
    More than one race
    2
    3.2%
    Unknown or Not Reported
    1
    1.6%
    Region of Enrollment (participants) [Number]
    United States
    62
    98.4%
    United Kingdom
    1
    1.6%

    Outcome Measures

    1. Primary Outcome
    Title Recurrence of Advanced Heart Block
    Description Echocardiogram reveals 2nd or 3rd degree AV 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)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pregnant Women With Previous Child With Cardiac Neonatal Lupus
    Arm/Group Description 400 mg/day Hydroxychloroquine 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.
    Measure Participants 63
    Count of Participants [Participants]
    5
    7.9%
    2. Secondary Outcome
    Title Prolonged PR Interval (>150msec)
    Description 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.
    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)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pregnant Women With Previous Child With Cardiac Neonatal Lupus
    Arm/Group Description 400 mg/day Hydroxychloroquine 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.
    Measure Participants 63
    Count of Participants [Participants]
    0
    0%
    3. Secondary Outcome
    Title Any Sign of Myocardial Injury, Without Change in Cardiac Rate or Rhythm
    Description 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.
    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)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pregnant Women With Previous Child With Cardiac Neonatal Lupus
    Arm/Group Description 400 mg/day Hydroxychloroquine 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.
    Measure Participants 63
    Count of Participants [Participants]
    0
    0%
    4. Secondary Outcome
    Title Echocardiographic Densities Consistent With EFE Confirmed Postnatally
    Description (see title)
    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)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pregnant Women With Previous Child With Cardiac Neonatal Lupus
    Arm/Group Description 400 mg/day Hydroxychloroquine 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.
    Measure Participants 63
    Count of Participants [Participants]
    0
    0%
    5. Secondary Outcome
    Title Fetal Death Not Related to Cardiac Dysfunction
    Description 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.
    Time Frame Up to 9 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pregnant Women With Previous Child With Cardiac Neonatal Lupus
    Arm/Group Description 400 mg/day Hydroxychloroquine 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.
    Measure Participants 63
    Count of Participants [Participants]
    0
    0%
    6. Secondary Outcome
    Title Cutaneous Neonatal Lupus
    Description
    Time Frame Up to 15 months (at birth - 9 months, and 6 months thereafter)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pregnant Women With Previous Child With Cardiac Neonatal Lupus
    Arm/Group Description 400 mg/day Hydroxychloroquine 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.
    Measure Participants 63
    Count of Participants [Participants]
    4
    6.3%
    7. Secondary Outcome
    Title Prematurity
    Description (gestational age <37 weeks at birth)
    Time Frame At birth (approximately 9 months)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pregnant Women With Previous Child With Cardiac Neonatal Lupus
    Arm/Group Description 400 mg/day Hydroxychloroquine 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.
    Measure Participants 63
    Count of Participants [Participants]
    9
    14.3%
    8. Secondary Outcome
    Title Birth Weight <10% in the Context of Gestational Age
    Description
    Time Frame At birth (approximately 9 months)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pregnant Women With Previous Child With Cardiac Neonatal Lupus
    Arm/Group Description 400 mg/day Hydroxychloroquine 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.
    Measure Participants 63
    Count of Participants [Participants]
    1
    1.6%
    9. Secondary Outcome
    Title Abnormal Fluid Collection
    Description
    Time Frame At birth (approximately 9 months)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pregnant Women With Previous Child With Cardiac Neonatal Lupus
    Arm/Group Description 400 mg/day Hydroxychloroquine 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.
    Measure Participants 63
    Count of Participants [Participants]
    0
    0%

    Adverse Events

    Time Frame From time of enrollment to six months after delivery.
    Adverse Event Reporting Description
    Arm/Group Title Pregnant Women With Previous Child With Cardiac Neonatal Lupus
    Arm/Group Description 400 mg/day Hydroxychloroquine 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.
    All Cause Mortality
    Pregnant Women With Previous Child With Cardiac Neonatal Lupus
    Affected / at Risk (%) # Events
    Total 0/63 (0%)
    Serious Adverse Events
    Pregnant Women With Previous Child With Cardiac Neonatal Lupus
    Affected / at Risk (%) # Events
    Total 0/63 (0%)
    Other (Not Including Serious) Adverse Events
    Pregnant Women With Previous Child With Cardiac Neonatal Lupus
    Affected / at Risk (%) # Events
    Total 11/63 (17.5%)
    Pregnancy, puerperium and perinatal conditions
    Maternal rash 2/63 (3.2%) 2
    Pre-eclampsia 2/63 (3.2%) 2
    Spontaneous miscarriage 1/63 (1.6%) 1
    Severe itching 1/63 (1.6%) 1
    Fall 1/63 (1.6%) 1
    Placental abruption 1/63 (1.6%) 1
    Placenta previa 1/63 (1.6%) 1
    Abnormal neonatal liver function test lab values 1/63 (1.6%) 1
    Right bundle branch block 1/63 (1.6%) 1

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Jill Buyon
    Organization NYU Langone Health
    Phone +1 212 263 0746
    Email Jill.Buyon@nyulangone.org
    Responsible Party:
    NYU Langone Health
    ClinicalTrials.gov Identifier:
    NCT01379573
    Other Study ID Numbers:
    • 11-00369
    First Posted:
    Jun 23, 2011
    Last Update Posted:
    Feb 25, 2021
    Last Verified:
    Feb 1, 2021