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

• ClinicalTrials.gov Identifier: NCT05764876
• Recruitment Status: Recruiting
• First Posted: March 13, 2023
• Last Update Posted: April 12, 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
• 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

Tracking Information

• First Submitted Date: February 2, 2023
• First Posted Date: March 13, 2023
• Last Update Posted Date: April 12, 2023
• Actual Study Start Date: March 14, 2023
• Estimated Primary Completion Date: May 1, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 10, 2023)

• 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.
• 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.
• 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.
• 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.
• 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 10, 2023)

• 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.
• 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.
• Plasma TPE assessment [ Time Frame: Baseline (before treatment) ]
  Assessment of TPE strains by genomic molecular methods in plasma from patients with active/latent yaws.
• 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.
• Identification of antibiotic resistance genotype. [ Time Frame: 4 weeks after treatment ]
  Proportion of patients with antibiotic resistance genotype.
• 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).
• Safety of intervention (adverse events) [ Time Frame: 48 weeks after treatment. ]
  Proportion of patients with adverse events

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Repurposing Clinically Approved Drugs for Yaws With an Insight Into the Cutaneous Ulcer Disease Syndrome (Trep-AByaws)
• Official Title: Repurposing Clinically Approved Drugs for Yaws With an Insight Into the Cutaneous Ulcer Disease Syndrome (Trep-AByaws)
• 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.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

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

Condition

• Yaws
• Cutaneous Ulcer

Intervention

• Drug: Linezolid Oral Tablet
  Oral tablet of linezolid 10mg/kg every 8 hours for 7 days.
  Other Name: Zyvox, Zyvoxid
• Drug: Azithromycin Oral Tablet
  Oral tablet of azithromycin 30mg/kg maximum 2gr single dose.
  Other Name: Zithromax

Study Arms

• Active Comparator: Azithromycin
  Participants in the control arm will receive standard treatment for yaws which azithromycin .
  Intervention: Drug: Azithromycin Oral Tablet
• Experimental: Linezolid
  Participants in the experimental arm will receive oral linezolid treatment.
  Intervention: Drug: Linezolid Oral Tablet

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 10, 2023): 360
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: May 1, 2024
• Estimated Primary Completion Date: May 1, 2024 (Final data collection date for primary outcome measure)

Eligibility 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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 5 Years to 18 Years (Child, Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Oriol Mitjà, MD, PhD; 0034609248887; omitja@lluita.org

Contact: Camila G Beiras, PhD; 0034609248887; cgonzalez@lluita.org

• Listed Location Countries: Papua New Guinea

Administrative Information

• NCT Number: NCT05764876
• Other Study ID Numbers: Trep-AByaws
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

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

• Current Responsible Party: Oriol Mitja, Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
• Original Responsible Party: Same as current
• Current Study Sponsor: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
• Original Study Sponsor: Same as current

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

• PRS Account: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
• Verification Date: April 2023