Congenital Syphilis Treatment Trial (CONSISTENT) in Neonates

Congenital Syphilis Treatment Trial (CONSISTENT): Phase IV, Open-label, Randomized Study of Oral Amoxicillin Twice Daily for 10 days vs Single Dose Intramuscular Benzathine Penicillin G in Infants with Possible Congenital Syphilis.

The Congenital Syphilis Treatment Trial (CONSISTENT) is a Phase IV, Open-label, Randomized Study of Oral (PO) Amoxicillin Twice Daily for 10 days vs Single Dose Intramuscular (IM) Benzathine Penicillin G (BPG) in Infants with Possible Congenital Syphilis (CS). It is designed as a multicenter, US, non-inferiority trial to test the treatment efficacy of amoxicillin PO compared with the standard of care BPG IM for possible CS. Infants will be eligible to participate based on active maternal syphilis diagnosed during pregnancy with inadequate maternal treatment and a negative complete neonatal evaluation including physical exam, CSF indices including negative VDRL, radiology (xray), and bloodwork for active syphilis in the first days after birth. The participants will be randomized with block randomization by site in a 1:1 manner to receive oral amoxicillin for 10 days or IM BPG once.

Samples for pharmacologic testing will be collected on a subgroup who choose to participate in an optional pharmacokinetic substudy to measure amoxicillin and BPG concentrations; participating infants in both arms will have plasma samples collected during the first 48 hours and at 10 days. Pre-treatment and post-treatment swabs will be taken from the oropharyngeal and nasal mucosal surfaces at day 1 and day 10 to detect the presence of T. pallidum using quantitative PCR, in addition to standard serologic syphilis antibody testing with quantitative rapid plasma reagin (RPR). Additional follow up visits will occur at days 60 and 180, with serum collected to assess the primary endpoint of serologic treatment response compared with baseline

Inclusion criteria

• Confirmed staged maternal syphilis in pregnancy with rapid plasma reagin (RPR) + and T. pallidum hemagglutination antibody (TPHA) or other evidence of active syphilis (i.e. ulcerative anogenital lesion with positive darkfield microscopy or PCR+ for T. pallidum)
• Inadequate therapy (non-BPG regimen, incomplete regimen for stage, <30 days prior to delivery), undocumented therapy, or lack of maternal syphilis therapy in pregnancy
• Infant age ≤ 30 days old
• Gestational age at birth ≥35 weeks
• Infant birth weight ≥ 750 grams
• Infant tolerating oral feeds
• Normal infant examination, laboratory, and radiographic evaluation: hemoglobin, platelet count, CSF (cell count, protein, VDRL), long-bone radiographs
• Infant quantitative RPR reactive and ≤ 4-fold lower titer compared with maternal RPR
• Parent(s) or legal guardian(s) capable and willing to provide informed consent

Exclusion criteria

• Infant receipt of antibiotics between birth and enrollment with activity against T. pallidum (including beta-lactam, cephalosporin, or azithromycin)
• Uncontrolled maternal HIV (viral load >1000 copies/mL at or within 4 weeks of delivery) or HIV-exposed infants who require three drug antiretroviral post exposure prophylaxis.
• Unable to ensure infant follow up through six months of age