Clinical trial NCT05764876: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Yaws
Cutaneous Ulcer
Keywords: azithromycin
linezolid
Lead sponsor: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
Sponsor class: OTHER
Collaborators: name: National Department of Health, Papua New Guinea
name: School of Medicine and Health Sciences, University of Papua New Guinea
First posted: 2023-03-13
Enrollment: 465
Sex: ALL
Minimum age (years): 5
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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).
Primary purpose: TREATMENT

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.

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).

Primary outcomes:
measure: Clinical resolution
timeFrame: 4 weeks after treatment
measure: Serological cure
timeFrame: 24 weeks after treatment
measure: Serological cure
timeFrame: 48 weeks after treatment
measure: Relapse
timeFrame: 24 weeks after treatment
measure: Relapse
timeFrame: 48 weeks after treatment
Secondary outcomes:
measure: Lession (ulcer swab) TPE assessment
timeFrame: Baseline (before treatment)
measure: Oral (oral swab) TPE assessment
timeFrame: Baseline (before treatment)
measure: Plasma TPE assessment
timeFrame: Baseline (before treatment)
measure: Allelic variation in recurrent cases
timeFrame: Baseline (before treatment)
measure: Identification of antibiotic resistance genotype.
timeFrame: 4 weeks after treatment
measure: Identification of other causes of cutaneous ulcer
timeFrame: Baseline (before treatment)
measure: Safety of intervention (adverse events)
timeFrame: 48 weeks after treatment.
Other outcomes:
Locations:
city: Port Moresby
country: Papua New Guinea
facility: National Department of Health
Study officials:
affiliation: Fundació Lluita contra les Infeccions
name: Camila Beiras
role: STUDY_DIRECTOR
References: