Congenital Syphilis Treatment Trial (CONSISTENT) in Neonates

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Syphilis, Congenital
• Intervention / Treatment: Drug: Benzathine Penicillin; Drug: Amoxicillin

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

• Study Type: Interventional
• Enrollment (Estimated): 374
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jill Griffin, MSN; Phone Number: 2056352537; Email: jillgriffin@uabmc.edu
• Study Contact Backup: Name: Linda Austin; Phone Number: 2056382530; Email: lpaustin@uabmc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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)
2. Inadequate therapy (non-BPG regimen, incomplete regimen for stage, <30 days prior to delivery), undocumented therapy, or lack of maternal syphilis therapy in pregnancy
3. Infant age ≤ 30 days old
4. Gestational age at birth ≥35 weeks
5. Infant birth weight ≥ 750 grams
6. Infant tolerating oral feeds
7. Normal infant examination, laboratory, and radiographic evaluation: hemoglobin, platelet count, CSF (cell count, protein, VDRL), long-bone radiographs
8. Infant quantitative RPR reactive and ≤ 4-fold lower titer compared with maternal RPR
9. Parent(s) or legal guardian(s) capable and willing to provide informed consent

Exclusion Criteria:

1. Infant receipt of antibiotics between birth and enrollment with activity against T. pallidum (including beta-lactam, cephalosporin, or azithromycin)
2. 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.
3. Unable to ensure infant follow up through six months of age

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Single Dose of BPG; Neonates will receive a single dose of BPG as standard of care.	Drug: Benzathine Penicillin; Standard of Care Treatment; Other Names: BPG
Experimental: Study Medication (Amoxicillin); Neonates will receive Amoxicillin (Study Medication), twice a day for 10 days.	Drug: Amoxicillin; Amoxicillin given by mouth for 10 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participants demonstrating a treatment efficacy of oral Amoxicillin BID X 10 days vs. BPG IM X1 by 6 months of age	Proportion with serologic response defined as RPR titer reversion to non-reactive or a four-fold decline in titer within one to six months after treatment.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportions of participants demonstrating a treatment efficacy	Serologic response defined as RPR titer reversion to non-reactive or a four-fold decline in titer at six months.	6 months
Rate of infant treatment response according to maternal syphilis stage (early/late).	Stratify infant treatment response according to dichotomized maternal syphilis stage (early/late) at the time of infant delivery.	30 days
Rate of infant treatment response according to the timing of maternal syphilis treatment.	Stratify infant treatment response according to timing of maternal treatment (within 30 d of delivery).	30 days
Rate of infant treatment response according to the type of treatment received by the mother during pregnancy.	Stratify infant treatment response according to type of treatment (BPG/non BPG).	30 days
Rate of Infant treatment response according to maternal HIV Status.	Stratify infant treatment response according to maternal HIV status.	30 days
Compare the incidence and manifestations of the Jarisch-Herxheimer reaction (JHR) among infants after amoxicillin vs BPG treatment for possible CS	Proportion of infants with JHR symptoms within 12-24 hours after the first dose of medication (amoxicillin or penicillin) with additional symptoms by self-report.	24 hours
Incidence of Treatment-Emergent Adverse Events	Incidence of Treatment-Emergent Adverse Events reported as moderate and severe AEs	40 days

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: David Kimberlin, MD, University of Alabama at Birmingham

Study record dates

Study Major Dates

• Study Start (Estimated): November 1, 2026
• Primary Completion (Estimated): May 1, 2031
• Study Completion (Estimated): August 31, 2031

Study Registration Dates

• First Submitted: February 25, 2026
• First Submitted That Met QC Criteria: March 3, 2026
• First Posted (Actual): March 9, 2026

Study Record Updates

• Last Update Posted (Actual): March 9, 2026
• Last Update Submitted That Met QC Criteria: March 3, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Infant, Newborn, Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Negative Bacterial Infections; Spirochaetales Infections; Treponemal Infections; Syphilis; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Syphilis, Congenital; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Amides; Penicillin G; beta-Lactams; Lactams; Ampicillin; Penicillins; Amoxicillin; Penicillin G Benzathine
• Other Study ID Numbers: CONSISTENT; Pending (Clinical Research Information Service)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes