Preventive Approach to Congenital Heart Block With Hydroxychloroquine (PATCH)
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.
Congenital Heart Block
Autoantibody-Associated Heart Block
|Study Design:||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|
- 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
- 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 ]
|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)|
Experimental: Pregnant women with previous child with cardiac neonatal lupus
400 mg/day 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
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01379573
|Contact: Jill P Buyon, MDemail@example.com|
|Contact: Tishaun Middleton, BAfirstname.lastname@example.org|
|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 email@example.com|
|Contact: Tishaun Middleton 646-501-0578 firstname.lastname@example.org|
|Principal Investigator: Jill P. Buyon, MD|
|Principal Investigator:||Jill P Buyon, MD||New York University School of Medicine|