Comprehensive Ambulatory Antibiotics for the Treatment of Congenital Syphilis (Cares-1)

CARES-1 is a randomised, open-label, phase II pharmacokinetic (PK) and safety study of ambulatory antibiotics for the treatment of neonates with "all-risk" asymptomatic congenital syphilis.

Study Overview

• Status: Recruiting
• Conditions: Syphilis, Congenital
• Intervention / Treatment: Drug: Linezolid (LZD); Drug: Amoxicillin; Drug: Benzathine Penicillin G

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sarah Prentice; Phone Number: +4420 7636 8636; Email: sarah.prentice@lshtm.ac.uk

Study Locations

• Indonesia
  • Jakarta, Indonesia
    • Not yet recruiting
    • Universitas Indonesia
    • Contact: Phoebe Williams; Phone Number: +61 2 9351 2222; Email: phoebe.williams@sydney.edu.au <phoebe.williams@sydney.edu.au>
• Malawi
  • Blantyre, Malawi
    • Not yet recruiting
    • Malawi Liverpool Wellcome Programme
    • Contact: Mary Mc Cauley; Phone Number: +265 111 81 19 18; Email: mmccauley@mlw.mw
• South Africa
  • Stellenbosch, South Africa
    • Recruiting
    • Stellenbosch
    • Contact: Lisa Frigati; Phone Number: +27 21 808 9111; Email: frigati@sun.ac.za

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Infants at risk of congenital syphilis at birth defined as:

   1. an infant born to a mother who tests positive for syphilis in pregnancy using registered and licensed locally-available diagnostic tests for example but not limited to a Treponemal rapid POCT, an RPR or both.

      AND

   2. the mother is untreated in the current pregnancy defined as:

   i. she tested positive at antenatal care and received no treatment OR ii. she was never tested during antenatal care OR iii. she tested negative at antenatal care and positive on re-testing at delivery

   OR c. the mother is inadequately treated in the current pregnancy defined as:

   i. Having received a non-penicillin based treatment regimen; and/or ii. Does not have documentation of 3 doses of IM Benzathine Penicillin, given 7-10 days apart, with the last dose given > 30 days prior to delivery OR b. The mother was adequately treated in the current pregnancy BUT considers herself at risk of re-infection following a midwife delivered explanation of risk (partner treatment, multiple partners etc).

2. Infants who are asymptomatic for a diagnosis of congenital syphilis following application of a clinical proforma by the study team (Appendix 1)
3. Infants who are less than <= 7 days of life AND with a post-menstrual age (PMA) of 34-42 weeks (Appendix 2).
4. Infants who are tolerating enteral feeds, including if they are being administered by an NG tube.

Exclusion Criteria:

- 1. The infant's clinical condition at birth or prior to randomisation requires ongoing (> 48 hours) treatment with antibiotics with the potential for anti-treponemal activity i.e. B-lactams, Cephalosporins, Carbapenems.

2. They have a birthweight <2kg 3. They are nil by mouth. 4. They have a life-limiting congenital anomaly

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oral Linezolid; 10 day course of Linezolid twice a day	Drug: Linezolid (LZD); Ten day course. Oral Linezolid dosed at 10mg/kg twice a day.
Experimental: Oral Amoxicillin; 10 day course of Amoxicillin twice a day	Drug: Amoxicillin; Ten day course. Oral Linezolid dosed at 50mg/kg twice a day.
Active Comparator: IM Benzathine penicillin; Single IM dose of IM Benzathine penicillin	Drug: Benzathine Penicillin G; Single IM dose 50,000iu/kg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time above MIC in serum	Time above MIC of T. pallidum for the dosing interval in serum	From enrolment through to day 10 of the study
Time above MIC in CSF	Time above MIC in CSF throughout the dosing interval	10 days
Adverse Events	The proportion of individuals experiencing an adverse event through to week 24. The trial will record SAE, SUSARS, and drug related AEs of grade 3 or higher.	Assessed from enrolment through to 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC/MIC Ratio in serum	Proportion of individuals achieving an AUC/MIC ratio ≥100 in serum	Enrolment through to day 10
AUC/MIC Ratio in CSF	Proportion of individuals achieving an AUC/MIC ratio ≥100 in CSF	Enrolment through to day 10
Clinical Outcome	Proportion of infants who have clinical or laboratory evidence of congenital syphilis as adjudicated by an expert committee, blinded to treatment allocation, based on clinical and laboratory data.	Enrolment through to week 24

Collaborators and Investigators

• Sponsor: London School of Hygiene and Tropical Medicine
• Collaborators: University College Dublin; University of Stellenbosch; University of Sydney; Murdoch Childrens Research Institute; MRC CTU at UCL; PHPT/AMS Laboratory, Faculty of Associated Medical Sciences, Chiang Mai University; Malawi Liverpool Wellcome Programme
• Investigators: Principal Investigator: Michael Marks, London School of Hygiene and Tropical Medicine; Principal Investigator: Bridget Freyne, University College Dublin

Study record dates

Study Major Dates

• Study Start (Actual): May 4, 2026
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: March 25, 2025
• First Submitted That Met QC Criteria: April 3, 2025
• First Posted (Actual): April 10, 2025

Study Record Updates

• Last Update Posted (Actual): May 11, 2026
• Last Update Submitted That Met QC Criteria: May 6, 2026
• Last Verified: May 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, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Azoles; Acids, Acyclic; Carboxylic Acids; Amides; beta-Lactams; Lactams; Acetamides; Acetates; Oxazolidinones; Oxazoles; Ampicillin; Penicillins; Linezolid; Amoxicillin; Penicillin G
• Other Study ID Numbers: 31732

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: At completion of the study an anonymised dataset will be deposited in an appropriate repository to facilitate sharing of IPD.
• IPD Sharing Time Frame: Following completion of the study
• IPD Sharing Access Criteria: Data will be available via a repository to other researchers
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

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