Congenital Syphilis Treatment Trial (CONSISTENT) in Neonates

Official title

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

Overview

The Investigator hypothesize that the treatment efficacy will be similar in both study arms. Secondary outcomes and endpoints will characterize safety by comparing adverse events (AEs), tolerability, and adherence to therapy in each arm. This is a Phase 4, open-label, multicenter trial designed to evaluate the efficacy of a single injected dose of intramuscular (IM) BPG (Arm 1) compared to oral amoxicillin administered twice daily (BID) for 10 days (Arm 2). The study will involve infants aged ≤ 30 days old with suspected untreated syphilis. The trial will be conducted at 12 sites across the U.S., enrolling approximately 374 participants. Upon randomization, participants will undergo baseline study sample collection (blood, oropharyngeal, and nasal mucosal swabs for PCR testing) and then receive either treatment with oral amoxicillin or IM BPG, both with directly observed therapy. The participant enrolled in the optional pharmacokinetic (PK) sub-study will have additional blood samples collected for PK analysis within the first 24-48 hours after treatment. Participants will be discharged from the hospital following routine procedures, with the oral amoxicillin dosing continued at home (BID) by the caregiver.

Detailed description

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

Interventions

• Drug Benzathine Penicillin
  Standard of Care Treatment
• Drug Amoxicillin
  Amoxicillin given by mouth for 10 days

Primary outcome measures

• Proportion of participants demonstrating a treatment efficacy of oral Amoxicillin BID X 10 days vs. BPG IM X1 by 6 months of age [Time frame: 6 months]

Secondary outcome measures (7)

• Proportions of participants demonstrating a treatment efficacy [Time frame: 6 months]
• Rate of infant treatment response according to maternal syphilis stage (early/late). [Time frame: 30 days]
• Rate of infant treatment response according to the timing of maternal syphilis treatment. [Time frame: 30 days]
• Rate of infant treatment response according to the type of treatment received by the mother during pregnancy. [Time frame: 30 days]
• Rate of Infant treatment response according to maternal HIV Status. [Time frame: 30 days]
• Compare the incidence and manifestations of the Jarisch-Herxheimer reaction (JHR) among infants after amoxicillin vs BPG treatment for possible CS [Time frame: 24 hours]
• Incidence of Treatment-Emergent Adverse Events [Time frame: 40 days]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Triple blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07457385 · CONSISTENT · Pending

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗