Repurposing Clinically Approved Drugs for Yaws With an Insight Into the Cutaneous Ulcer Disease Syndrome (Trep-AByaws) (Trep-AByaws)

The goal of this clinical trial is to test the non inferiority of linezolid compared with azithromycin as a treatment for yaws . The main questions it aims to answer are: can linezolid cure active yaws, and can linezolid cure latent yaws. Participants with serologically confirmed yaws will be randomized to receive linezolid (experimental) or azithromycin (control group) treatment and followed up to assess clinical resolution.

Study Overview

• Status: Recruiting
• Conditions: Yaws; Cutaneous Ulcer
• Intervention / Treatment: Drug: Azithromycin Oral Tablet; Drug: Linezolid Oral Tablet

Detailed Description

The current principle of yaws eradication is based on a single round of mass drug administration of azithromycin (AZI) called total community treatment (TCT) followed by targeted treatment of active cases and close contacts every 6 months called total targeted treatment (TTT). Studies done in Papua New Guinea have shown that 3 rounds of TCT are preferable to 1 TCT followed by TTT rounds because it results in higher overall coverage, particularly of latent cases. In the context of repeated rounds of TTT and multiple rounds of TCT, resistance to AZI has ben detected on 5 patients with yaws Recent studies have been successful on the culture of Treponema pallidum (syphilis and yaws), therefore investigators are now able to identify more potential treatment for yaws and syphilis.

Yaws is one of the major causes of the Cutaneous Ulcer Disease (CUD) syndrome. The CUD syndrome is a painful and debilitating condition, endemic to remote tropical regions with poor sanitation and limited health care access affecting children mainly. In Papua New Guinea it is caused by a range of unknown and some known pathogens besides yaws that are not easily distinguished on clinical diagnosis. New information on the causative agents of the CUD syndrome is needed to facilitate its management with an integrated approach.

The aim of the project is to provide evidence supporting (or rejecting) the hypothesis that the use of linezolid (LZD) can be an alternative treatment to cure yaws corroborated by clinical, serological, and molecular methods. LZD is a very safe drug that has been delivered to adults and children for the treatment of cutaneous infections all over the world. Investigators will compare two different treatments: (A) linezolid (LZD) and (B) azithromycin (AZI). In addition, the investigators plan to contribute to characterize the etiology of the CUD syndrome. The study will be implemented in selected wards of the Islands Region of Papua New Guinea.

• Study Type: Interventional
• Enrollment (Anticipated): 360
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Oriol Mitjà, MD, PhD; Phone Number: 0034609248887; Email: omitja@lluita.org
• Study Contact Backup: Name: Camila G Beiras, PhD; Phone Number: 0034609248887; Email: cgonzalez@lluita.org

Study Locations

• Papua New Guinea
  • Port Moresby, Papua New Guinea
    • Recruiting
    • National Department of Health
    • Contact: Wendy Houinei, HEO; Phone Number: +675 7124 7511; Email: whouinei@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Participants 5-18 years identified during an active case search program at the elementary, primary and secondary schools in the Islands Region.
2. CUD syndrome suspected due to yaws: one or more ulcerative or nodular or papilloma skin lesion of more than 1 cm in diameter.
3. Positive treponemal (T1) and non-treponemal (T2) serology by Chembio dual path platform (DPP) syphilis screen & confirm assay (DPP test).
4. Accepted and signed informed consent.
5. Ability to comply with the requirements of the study protocol including follow up visits.

Exclusion Criteria:

1. Children younger than 5 years old.
2. Clinical late-stage possible yaws: destructive osteitis (rhinopharyngitis gangosa, sabre shins) or gummous nodules.
3. Known allergy to LZD or AZI antibiotics.
4. Pregnant or breastfeeding women.
5. Refusal at ward level or village chief (for village inclusion), or refusal of individual or guardian (for individual inclusion).
6. Have taken any antibiotics with potential activity against TPE within the last 7 days prior to randomization (i.e., beta lactams, cephalosporines, macrolides, tetracyclines).
7. Uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, carcinoid syndrome, bipolar disorder, incapacitating psycho-affective disturbance, acute confusional state.
8. Renal function impairment requiring hemodialysis.
9. Current treatment with any drugs likely to interact with the study medication
10. Symptomatic concomitant infection requiring antibiotic treatment potentially active against TPE.
11. Having received treatment for yaws in the last 6 months.
12. Patients who are unable to take oral medication or having a gastrointestinal disease likely to interfere with drug absorption (including malnutrition and stomach flu).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Azithromycin; Participants in the control arm will receive standard treatment for yaws which azithromycin .	Drug: Azithromycin Oral Tablet; Oral tablet of azithromycin 30mg/kg maximum 2gr single dose.; Other Names: Zithromax
Experimental: Linezolid; Participants in the experimental arm will receive oral linezolid treatment.	Drug: Linezolid Oral Tablet; Oral tablet of linezolid 10mg/kg every 8 hours for 7 days.; Other Names: Zyvox, Zyvoxid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical resolution	Proportion of patients with clinical resolution of yaws lesions (clinical cure). Assessment of clinical resolution defined as the complete healing of lesions at 4 weeks from treatment start.	4 weeks after treatment
Serological cure	Proportion of patients with adequate serological response (serological cure). Assessment of sero-cure is described as a four-fold decline in rapid plasma reagin (RPR) titer or seroreversion at 24 weeks from treatment start.	24 weeks after treatment
Serological cure	Proportion of patients with adequate serological response (serological cure). Assessment of sero-cure is described as a four-fold decline in rapid plasma reagin (RPR) titer or seroreversion at 48 weeks from treatment start.	48 weeks after treatment
Relapse	Proportion of patients with relapse (recurrent episodes caused by the same strain) (molecular cure). Assessment of recurrence by molecular methods of Treponema pallidum ssp. pertenue (TPE) DNA in ulcer swab to determine relapse or reinfection within 24 weeks from treatment start.	24 weeks after treatment
Relapse	Proportion of patients with relapse (recurrent episodes caused by the same strain) (molecular cure). Assessment of recurrence by molecular methods of Treponema pallidum ssp. pertenue (TPE) DNA in ulcer swab to determine relapse or reinfection within 48 weeks from treatment start.	48 weeks after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lession (ulcer swab) TPE assessment	Assessment of TPE strains by genomic molecular methods in ulcer swabs from patients with active yaws.	Baseline (before treatment)
Oral (oral swab) TPE assessment	Assessment of TPE strains by genomic molecular methods in oral swabs from patients with active/latent yaws.	Baseline (before treatment)
Plasma TPE assessment	Assessment of TPE strains by genomic molecular methods in plasma from patients with active/latent yaws.	Baseline (before treatment)
Allelic variation in recurrent cases	Proportion of patients with allelic variation in TPE DNA in patients with recurrence or treatment failure.	Baseline (before treatment)
Identification of antibiotic resistance genotype.	Proportion of patients with antibiotic resistance genotype.	4 weeks after treatment
Identification of other causes of cutaneous ulcer	Proportion of patients with selected known and unknown causes of cutaneous ulcers (CU). Assessment of etiological agents using polymerase chain reaction (PCR) for TPE, Haemophylus ducreyi (HD) and Streptoccocus pyogenes (SP).	Baseline (before treatment)
Safety of intervention (adverse events)	Proportion of patients with adverse events	48 weeks after treatment.

Collaborators and Investigators

• Sponsor: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
• Collaborators: National Department of Health, Papua New Guinea; School of Medicine and Health Sciences, University of Papua New Guinea
• Investigators: Study Director: Camila Beiras, Fundació Lluita contra les Infeccions

Study record dates

Study Major Dates

• Study Start (Actual): March 14, 2023
• Primary Completion (Anticipated): May 1, 2024
• Study Completion (Anticipated): May 1, 2024

Study Registration Dates

• First Submitted: February 2, 2023
• First Submitted That Met QC Criteria: March 10, 2023
• First Posted (Actual): March 13, 2023

Study Record Updates

• Last Update Posted (Actual): April 12, 2023
• Last Update Submitted That Met QC Criteria: April 11, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: azithromycin; linezolid
• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Ulcer; Skin Ulcer; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Linezolid; Azithromycin
• Other Study ID Numbers: Trep-AByaws

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Protocol and anonymised data will be made available upon reasonable request

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