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

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ClinicalTrials.gov Identifier: NCT05764876
Recruitment Status : Recruiting
First Posted : March 13, 2023
Last Update Posted : April 12, 2023
Sponsor:
Collaborators:
National Department of Health, Papua New Guinea
School of Medicine and Health Sciences, University of Papua New Guinea
Information provided by (Responsible Party):
Oriol Mitja, Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia

Study Description
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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.

Condition or disease Intervention/treatment Phase
Yaws Cutaneous Ulcer Drug: Linezolid Oral Tablet Drug: Azithromycin Oral Tablet Phase 3

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 360 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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: Single (Investigator)
Masking Description: Investigator will not be present for treatment nor for outcome assessment, and data analysis (statistics) will be blinded.
Primary Purpose: Treatment
Official Title: Repurposing Clinically Approved Drugs for Yaws With an Insight Into the Cutaneous Ulcer Disease Syndrome (Trep-AByaws)
Actual Study Start Date : March 14, 2023
Estimated Primary Completion Date : May 1, 2024
Estimated Study Completion Date : May 1, 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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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 Name: 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 Name: Zyvox, Zyvoxid


Outcome Measures
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Primary Outcome Measures :
  1. Clinical resolution [ Time Frame: 4 weeks after treatment ]
    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.

  2. Serological cure [ Time Frame: 24 weeks after treatment ]
    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.

  3. Serological cure [ Time Frame: 48 weeks after treatment ]
    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.

  4. Relapse [ Time Frame: 24 weeks after treatment ]
    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.

  5. Relapse [ Time Frame: 48 weeks after treatment ]
    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 :
  1. Lession (ulcer swab) TPE assessment [ Time Frame: Baseline (before treatment) ]
    Assessment of TPE strains by genomic molecular methods in ulcer swabs from patients with active yaws.

  2. Oral (oral swab) TPE assessment [ Time Frame: Baseline (before treatment) ]
    Assessment of TPE strains by genomic molecular methods in oral swabs from patients with active/latent yaws.

  3. Plasma TPE assessment [ Time Frame: Baseline (before treatment) ]
    Assessment of TPE strains by genomic molecular methods in plasma from patients with active/latent yaws.

  4. Allelic variation in recurrent cases [ Time Frame: Baseline (before treatment) ]
    Proportion of patients with allelic variation in TPE DNA in patients with recurrence or treatment failure.

  5. Identification of antibiotic resistance genotype. [ Time Frame: 4 weeks after treatment ]
    Proportion of patients with antibiotic resistance genotype.

  6. Identification of other causes of cutaneous ulcer [ Time Frame: Baseline (before treatment) ]
    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).

  7. Safety of intervention (adverse events) [ Time Frame: 48 weeks after treatment. ]
    Proportion of patients with adverse events


Eligibility Criteria
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Ages Eligible for Study:   5 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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).
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05764876


Contacts
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Contact: Oriol Mitjà, MD, PhD 0034609248887 omitja@lluita.org
Contact: Camila G Beiras, PhD 0034609248887 cgonzalez@lluita.org

Locations
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Papua New Guinea
National Department of Health Recruiting
Port Moresby, Papua New Guinea
Contact: Wendy Houinei, HEO    +675 7124 7511    whouinei@gmail.com   
Sponsors and Collaborators
Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
National Department of Health, Papua New Guinea
School of Medicine and Health Sciences, University of Papua New Guinea
Investigators
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Study Director: Camila Beiras Fundació Lluita contra les Infeccions
More Information
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Responsible Party: Oriol Mitja, Associate Professor, Infectious Diseases and Global Health, Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
ClinicalTrials.gov Identifier: NCT05764876    
Other Study ID Numbers: Trep-AByaws
First Posted: March 13, 2023    Key Record Dates
Last Update Posted: April 12, 2023
Last Verified: April 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Protocol and anonymised data will be made available upon reasonable request

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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
Keywords provided by Oriol Mitja, Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia:
azithromycin
linezolid
Additional relevant MeSH terms:
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Skin Ulcer
Ulcer
Pathologic Processes
Skin Diseases
Azithromycin
Linezolid
 Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action