Preventive IVIG Therapy for Congenital Heart Block
Information source: New York University School of Medicine
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Congenital Heart Block; Neonatal Lupus; Autoantibody-Associated Heart Block
Intervention: intravenous immune globulin (IVIG) (Drug)
Phase: Phase 2/Phase 3
Sponsored by: New York University School of Medicine
Official(s) and/or principal investigator(s):
Jill P. Buyon, MD, Principal Investigator, Affiliation: New York University School of Medicine
Neonatal lupus (NL) is the name given to a group of conditions that can affect the babies of
mothers who have certain autoantibodies against components of the body's cells that are
called SSA/Ro and SSB/La. NL can appear as a temporary rash that usually goes away by the
time the baby is 6 months old, or very rarely an abnormal blood or liver condition that also
improves with time - or it can cause permanent and often life-threatening damage to the
fetal heart, known as congenital heart block (CHB). In women with anti-Ro/La antibodies who
are pregnant for the first time, only about 2% of the babies will develop CHB. But for a
woman who has already had a child with CHB or NL rash, the risk of CHB in her next pregnancy
is nearly 20%. Unfortunately, once complete (third degree) heart block has been
unequivocally identified in a fetus, it has never been reversed with any of the therapies
that have been tried to date. Our previous studies strongly indicate that scarring of the
conduction system (the heart's own natural "pacemaker"), a consequence of inflammation
triggered by the mother's antibodies, damages or even destroys the cells that allow the
heart to beat at a normal rhythm. Instead, the damaged heart beats extremely slowly, to an
extent that is fatal to nearly 20% of affected babies (with most deaths occurring as fetal
demises). Nearly all surviving children with CHB require permanent implantation of a
pacemaker device. Because it is so difficult to treat or repair the damaged heart, a
high-priority strategy is to try to prevent the inflammatory process before irreversible
scarring can occur. The aim of this clinical-based proposal is to determine whether treating
the pregnant mother with intravenous immune globulin (IVIG) will prevent the development of
Official title: Preventive IVIG Therapy for Congenital Heart Block (The PITCH Study)
Study design: Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention
Primary outcome: 2nd or 3rd degree heart block
Prolonged PR interval (>0.150 sec)
Sign of myocardial injury, w/o change in heart rate/rhythm
Echocardiographic density consistent with EFE
Rash consistent w neonatal lupus
Gestational age at birth
Abnormal fluid collection
Perhaps the strongest clinical association with autoantibodies against SSA/Ro-SSB/La is the
development of congenital heart block (CHB) in an offspring, an alarming prospect facing 2%
of primigravid mothers with these antibodies. Recurrence rates approach 20%. Disease can
progress rapidly, with advanced block and life-threatening cardiomyopathy observed less than
2 weeks from normal sinus rhythm. Once 3rd degree (complete) block is identified, reversal
has never been achieved, despite dexamethasone. This makes biologic sense since the
signature lesion is fibrosis of the atrioventricular node. Thus, strategies aimed at
preventing disease assume high priority. Although disease expression in the fetus requires
additional factors to amplify the cascade to fibrosis, maternal anti-Ro/La antibodies are
necessary. Accordingly, eliminating fetal exposure to these antibodies is a sound and
important approach. Intravenous immune globulin (IVIG) is particularly exciting in its
potential not only to lower maternal antibody levels (which is not accomplished with
glucocorticoids or immunosuppression), but actually to influence effector mechanisms in the
fetus itself. Aim 1 is a clinical trial to assess the efficacy of IVIG in preventing CHB.
Proof of efficacy is challenging since CHB occurs in only 2% of first pregnancies of
anti-Ro/La+ women. However, given the 10-fold higher risk of CHB in a pregnancy after the
birth of child with neonatal lupus (NL), mothers with previous NL-affected children are the
target population for study. Sample size calculations employ Simon's 2-stage optimal design.
Based on a 2-sided significance level of 0. 05, a power of 90% to show reduction of risk to
5% given the prediction that 18% of untreated subjects will get some degree of CHB, Stage 1
will enroll 19 women who have had a previous child with CHB or NL rash, to receive IVIG (400
mg/kg IVIG every 3 weeks for a total of 5 treatments) from weeks 12 through 24 of gestation.
If fewer than 3 mothers have children with 2nd or 3rd degree block, then an additional 35
mothers will be enrolled in Stage 2 (total = 54 subjects). IVIG will be considered
efficacious and worthy of further study if fewer than 6 of 54 subjects have a child with
advanced CHB. Secondary outcomes include 1st degree block, myocardial injury absent
conduction defects, and isolated endocardial fibroelastosis as assessed by serial fetal
echocardiograms and EKG at birth.
Aim 2 will address: a) the effect of IVIG on antibody titer and subclass; b) genetic
polymorphisms in Fc gamma receptor (FcgR) and platelet-activating factor acetylhydrolase and
their potential association with response to IVIG; c) whether a decrease in anti-La
antibodies positively correlates with the level of anti-La antiidiotypic antibodies; d)
whether IVIG blocks expression of activation markers on human macrophages after challenge
with opsonized apoptotic cardiocytes and whether this positively correlates with increased
expression of the inhibitory Fc receptor, FcgRIIb.
In sum, IVIG is a promising agent that may have effects at several levels of the pathologic
cascade to antibody-mediated CHB.
Minimum age: 18 Years.
Maximum age: 50 Years.
- Mother must currently have an intrauterine pregnancy of less than 12 weeks.
- Mother must have antibodies to SSA/Ro and/or SSB/La (will be confirmed in the
clinical immunology laboratory at the Principal Investigator's institution, the
NYU-Hospital for Joint Diseases).
- Mother can be asymptomatic or have any rheumatic disease (such as lupus, Sjogren
syndrome or other).
- Mother must have had a previous child with one of the following: (a) congenital heart
block (any degree) documented by EKG if live birth and/or echocardiogram if fetal
demise; (b) characteristic neonatal lupus rash confirmed by photograph revealing
annular lesions (evaluated by the PI), dermatology note, and/or biopsy; (c)
congenital heart block and rash.
- Mother may be taking 20 mg prednisone per day or less.
- Mother does not have antibodies to either SSA/Ro or SSB/La.
- Mother is taking greater than 20 mg prednisone per day.
- Mother has any condition that would contraindicate the use of IVIG: (a) prior
serious reaction to IVIG infusion; (b) known IgA deficiency; (c) intolerance of
volume load, e. g., congestive heart failure; (d) nephrotic syndrome.
- Identification in the fetus of any of the following structural lesions considered
causal for congenital heart block: (a) atrioventricular septal defects; (b) single
ventricle; (c) developmental tricuspid valve disease; (d) L-transposition of the
great arteries; (e) heterotaxia.
Locations and Contacts
Saint Barnabas Medical Center, Livingston, New Jersey 07039, United States
New York University School of Medicine / NYU-Hospital for Joint Diseases, New York, New York 10016, United States
Starting date: April 2007
Last updated: June 23, 2009