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

Primary Purpose

Yaws, Cutaneous Ulcer

Status
Recruiting
Phase
Phase 3
Locations
Papua New Guinea
Study Type
Interventional
Intervention
Linezolid Oral Tablet
Azithromycin Oral Tablet
Sponsored by
Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Yaws focused on measuring azithromycin, linezolid

Eligibility Criteria

5 Years - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Participants 5-18 years identified during an active case search program at the elementary, primary and secondary schools in the Islands Region. CUD syndrome suspected due to yaws: one or more ulcerative or nodular or papilloma skin lesion of more than 1 cm in diameter. Positive treponemal (T1) and non-treponemal (T2) serology by Chembio dual path platform (DPP) syphilis screen & confirm assay (DPP test). Accepted and signed informed consent. Ability to comply with the requirements of the study protocol including follow up visits. Exclusion Criteria: Children younger than 5 years old. Clinical late-stage possible yaws: destructive osteitis (rhinopharyngitis gangosa, sabre shins) or gummous nodules. Known allergy to LZD or AZI antibiotics. Pregnant or breastfeeding women. Refusal at ward level or village chief (for village inclusion), or refusal of individual or guardian (for individual inclusion). Have taken any antibiotics with potential activity against TPE within the last 7 days prior to randomization (i.e., beta lactams, cephalosporines, macrolides, tetracyclines). Uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, carcinoid syndrome, bipolar disorder, incapacitating psycho-affective disturbance, acute confusional state. Renal function impairment requiring hemodialysis. Current treatment with any drugs likely to interact with the study medication Symptomatic concomitant infection requiring antibiotic treatment potentially active against TPE. Having received treatment for yaws in the last 6 months. Patients who are unable to take oral medication or having a gastrointestinal disease likely to interfere with drug absorption (including malnutrition and stomach flu).

Sites / Locations

  • National Department of HealthRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Azithromycin

Linezolid

Arm Description

Participants in the control arm will receive standard treatment for yaws which azithromycin .

Participants in the experimental arm will receive oral linezolid treatment.

Outcomes

Primary Outcome Measures

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.
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.
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.
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.
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.

Secondary Outcome Measures

Lession (ulcer swab) TPE assessment
Assessment of TPE strains by genomic molecular methods in ulcer swabs from patients with active yaws.
Oral (oral swab) TPE assessment
Assessment of TPE strains by genomic molecular methods in oral swabs from patients with active/latent yaws.
Plasma TPE assessment
Assessment of TPE strains by genomic molecular methods in plasma from patients with active/latent yaws.
Allelic variation in recurrent cases
Proportion of patients with allelic variation in TPE DNA in patients with recurrence or treatment failure.
Identification of antibiotic resistance genotype.
Proportion of patients with antibiotic resistance genotype.
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).
Safety of intervention (adverse events)
Proportion of patients with adverse events

Full Information

First Posted
February 2, 2023
Last Updated
April 11, 2023
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
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1. Study Identification

Unique Protocol Identification Number
NCT05764876
Brief Title
Repurposing Clinically Approved Drugs for Yaws With an Insight Into the Cutaneous Ulcer Disease Syndrome (Trep-AByaws)
Acronym
Trep-AByaws
Official Title
Repurposing Clinically Approved Drugs for Yaws With an Insight Into the Cutaneous Ulcer Disease Syndrome (Trep-AByaws)
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 14, 2023 (Actual)
Primary Completion Date
May 1, 2024 (Anticipated)
Study Completion Date
May 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the 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

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Yaws, Cutaneous Ulcer
Keywords
azithromycin, linezolid

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Open-label, non inferiority, two arms and randomized clinical trial. Eligible patients will be randomized (1:1) to receive Linezolid (experimental arm) or Azithromycin (control arm).
Masking
Investigator
Masking Description
Investigator will not be present for treatment nor for outcome assessment, and data analysis (statistics) will be blinded.
Allocation
Randomized
Enrollment
360 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Azithromycin
Arm Type
Active Comparator
Arm Description
Participants in the control arm will receive standard treatment for yaws which azithromycin .
Arm Title
Linezolid
Arm Type
Experimental
Arm Description
Participants in the experimental arm will receive oral linezolid treatment.
Intervention Type
Drug
Intervention Name(s)
Linezolid Oral Tablet
Other Intervention Name(s)
Zyvox, Zyvoxid
Intervention Description
Oral tablet of linezolid 10mg/kg every 8 hours for 7 days.
Intervention Type
Drug
Intervention Name(s)
Azithromycin Oral Tablet
Other Intervention Name(s)
Zithromax
Intervention Description
Oral tablet of azithromycin 30mg/kg maximum 2gr single dose.
Primary Outcome Measure Information:
Title
Clinical resolution
Description
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.
Time Frame
4 weeks after treatment
Title
Serological cure
Description
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.
Time Frame
24 weeks after treatment
Title
Serological cure
Description
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.
Time Frame
48 weeks after treatment
Title
Relapse
Description
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.
Time Frame
24 weeks after treatment
Title
Relapse
Description
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.
Time Frame
48 weeks after treatment
Secondary Outcome Measure Information:
Title
Lession (ulcer swab) TPE assessment
Description
Assessment of TPE strains by genomic molecular methods in ulcer swabs from patients with active yaws.
Time Frame
Baseline (before treatment)
Title
Oral (oral swab) TPE assessment
Description
Assessment of TPE strains by genomic molecular methods in oral swabs from patients with active/latent yaws.
Time Frame
Baseline (before treatment)
Title
Plasma TPE assessment
Description
Assessment of TPE strains by genomic molecular methods in plasma from patients with active/latent yaws.
Time Frame
Baseline (before treatment)
Title
Allelic variation in recurrent cases
Description
Proportion of patients with allelic variation in TPE DNA in patients with recurrence or treatment failure.
Time Frame
Baseline (before treatment)
Title
Identification of antibiotic resistance genotype.
Description
Proportion of patients with antibiotic resistance genotype.
Time Frame
4 weeks after treatment
Title
Identification of other causes of cutaneous ulcer
Description
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).
Time Frame
Baseline (before treatment)
Title
Safety of intervention (adverse events)
Description
Proportion of patients with adverse events
Time Frame
48 weeks after treatment.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
5 Years
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Participants 5-18 years identified during an active case search program at the elementary, primary and secondary schools in the Islands Region. CUD syndrome suspected due to yaws: one or more ulcerative or nodular or papilloma skin lesion of more than 1 cm in diameter. Positive treponemal (T1) and non-treponemal (T2) serology by Chembio dual path platform (DPP) syphilis screen & confirm assay (DPP test). Accepted and signed informed consent. Ability to comply with the requirements of the study protocol including follow up visits. Exclusion Criteria: Children younger than 5 years old. Clinical late-stage possible yaws: destructive osteitis (rhinopharyngitis gangosa, sabre shins) or gummous nodules. Known allergy to LZD or AZI antibiotics. Pregnant or breastfeeding women. Refusal at ward level or village chief (for village inclusion), or refusal of individual or guardian (for individual inclusion). Have taken any antibiotics with potential activity against TPE within the last 7 days prior to randomization (i.e., beta lactams, cephalosporines, macrolides, tetracyclines). Uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, carcinoid syndrome, bipolar disorder, incapacitating psycho-affective disturbance, acute confusional state. Renal function impairment requiring hemodialysis. Current treatment with any drugs likely to interact with the study medication Symptomatic concomitant infection requiring antibiotic treatment potentially active against TPE. Having received treatment for yaws in the last 6 months. Patients who are unable to take oral medication or having a gastrointestinal disease likely to interfere with drug absorption (including malnutrition and stomach flu).
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Oriol Mitjà, MD, PhD
Phone
0034609248887
Email
omitja@lluita.org
First Name & Middle Initial & Last Name or Official Title & Degree
Camila G Beiras, PhD
Phone
0034609248887
Email
cgonzalez@lluita.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Camila Beiras
Organizational Affiliation
Fundació Lluita contra les Infeccions
Official's Role
Study Director
Facility Information:
Facility Name
National Department of Health
City
Port Moresby
Country
Papua New Guinea
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Wendy Houinei, HEO
Phone
+675 7124 7511
Email
whouinei@gmail.com

12. IPD Sharing Statement

Plan to Share IPD
Undecided
IPD Sharing Plan Description
Protocol and anonymised data will be made available upon reasonable request

Learn more about this trial

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

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