Congenital Syphilis Treatment Trial (CONSISTENT): Phase IV, Open-label, Randomized Controlled Trial of Amoxicillin vs Benzathine Penicillin in Neonates with Possible Congenital Syphilis

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Project Summary/Abstract Syphilis is caused by Treponema pallidum (T. pallidum) that can efficiently cross the placenta during all stages of pregnancy and cause fetal infection. In the absence of timely diagnosis and treatment in pregnancy, congenital syphilis (CS) can occur. CS rates have risen sharply in every region of the US over the past decade. Possible congenital syphilis is defined by in-utero exposure to syphilis in an asymptomatic infant with a negative syphilis evaluation (exam, CSF, CBC, and RPR ≤ 4-fold maternal RPR). Recommended treatment for possible CS is single dose benzathine penicillin G (BPG), an effective therapy that has intermittent shortages. The Congenital Syphilis Treatment Trial (CONSISTENT) was designed to test the efficacy of oral amoxicillin therapy (50 mg/kg po BID) compared to standard single dose intramuscular BPG therapy (50,000 u/kg) measured by serologic response within 6 months of treatment. CONSISTENT is a phase IV, open-label, randomized study that will enroll 374 infants (≥35 weeks) at twelve US clinical sites over a two-year enrollment period. Participants will be invited to participate in an optional pharmacokinetic substudy (n=30), and will have pre- and post-treatment oral/nasal swabs collected for T. pallidum PCR testing to carry out the following aims: Aim 1: Compare the treatment efficacy of liquid oral amoxicillin administered BID x 10 days compared to single dose IM BPG (standard of care) among 374 neonates with possible congenital syphilis; Aim 2: Confirm the oral amoxicillin dose of 50 mg/kg/dose BID for the treatment of congenital syphilis using the target plasma drug concentration of 0.42 mg/L as the MIC for T. pallidum; Aim 3: Assess the performance of quantitative PCR testing for T. pallidum on oropharyngeal and nasal swabs in refining the diagnosis of possible congenital syphilis in exposed neonates. Aim 1 will test the hypothesis that amoxicillin efficacy will be non-inferior (within a 10% margin) compared with standard IM BPG for the treatment of possible CS assessed by serologic RPR response within six months. Aim 2 will test the hypothesis that oral amoxicillin 50 mg/kg/dosed BID will be sufficient to maintain drug levels above the MIC threshold required to treat possible congenital syphilis. Aim 3 will test our hypothesis that newly developed quantitative PCR testing of easily collected oropharyngeal and nasal swabs will help refine and improve the diagnosis of syphilis in infants. Our expected outcome is to identify an alternative oral treatment option for infants with possible congenital syphilis. Our long-term goals are to improve options for the treatment and diagnosis of syphilis in infants to reduce long term adverse outcomes.