Single-dose Azithromycin for the Treatment of Yaws
Condition: Yaws; Treponema Infection; Neglected Tropical Disease
MeSH terms: Treponemal Infections
Study type: Interventional
Phase: Phase 3

Summary: 
      Yaws, an endemic treponematosis and as such a neglected tropical disease (NTD), is currently
      making a comeback in children in rural areas. Injectable long acting penicillin remains the
      drug of choice for the treatment of yaws. However, on the basis of successful experience with
      venereal syphilis in large-scale studies, oral azithromycin has emerged as a potential
      alternative that overcomes the major medical and logistic disadvantages of the current
      regimen.

      In this non-inferiority randomized clinical trial the investigators propose a comparable
      scheme for the treatment of yaws, to test the efficacy of a single, oral dose of azithromycin
      versus a single, i.m. dose of benzathine penicillin G.Sample size has been calculated to
      detect a non-inferiority margin of 10%. Children < 15 years of age with a confirmed diagnosis
      of yaws will be randomly assigned to receive 30mg/Kg (maximum 2g) of azithromycin orally or
      50.000units/Kg (maximum 2.4MU) of penicillin-G-benzathine intramuscularly. The primary
      outcome is treatment efficacy, with cure defined serologically (a decline in the VDRL titer
      of at least two dilutions by six months after treatment) and, in primary yaws, also by
      epithelialization of ulcers within two weeks.
    

Detailed description: 
      Regulatory status: Investigational - Randomized Clinical Trial. Registered product for
      antibacterial therapy

      BACKGROUND Penicillin remains the drug of choice for the treatment of endemic treponematoses
      including yaws. This type of treatment is effective and cheap. There are, however, some
      disadvantages: the pain associated with a large volume (4 ml) deep i.m. injection, a high
      prevalence of self-reported allergy to penicillin, structural and logistic problems related
      to a treatment based on injection of drugs.

      Azithromycin, a macrolide antibiotic with a long (68 hours) half-life in tissue and proven
      efficacy against T.pallidum is a promising candidate. In two randomized trials, for the
      treatment of syphilis in adults, a single 2-g oral dose of azithromycin achieved cure rates
      equivalent to that of standard treatment with 2.4 MU of penicillin G benzathine. On the basis
      of experience with venereal syphilis, azithromycin has emerged as an alternative treatment
      for Yaws. It represents a more accessible treatment as it could be prescribed by village
      health workers and therefore enable yaws control to be more easily incorporated into other
      primary health-care programmes.

      The product is available as an oral tablet to be administered at a single dose of 30mg/Kg in
      children and 2 g in adults. Safety and efficacy using azithromycin 30 mg/kg given as a single
      dose in the treatment of pediatric patients over 6 months of age with otitis media have been
      established and approved by the FDA.

      INFORMED CONSENT All participants (or their guardian or parents) who are eligible for
      enrolment in the trial according to biological and demographic inclusion criteria are
      provided with detailed information on the purpose of the trial and on risks and benefits of
      participation, according to information listed in an information sheet. Consent is provided
      in writing.

      SAMPLE SIZE JUSTIFICATION

      The sample size would be 244; It was calculated on the basis of a non-inferiority trial
      design and the following assumptions:

      Statistical power of 80 percent;to exclude the possibility that the absolute efficacy of
      azithromycin was at least 10% percent less than that of penicillin; 5% significance level
      using a one-sided equivalence test of proportions; assuming that the true efficacy of each
      agent was equivalent at 95 percent and that approximately 10 percent of participants would be
      lost to follow-up.

      RANDOMIZATION PROCEDURE A random allocation schedule, stratified according to study group,
      will be generated centrally with the use of blocked randomization, random permuted blocks of
      four, and a 1:1 allocation ratio. The allocation will be concealed from investigators through
      the use of sequentially numbered, sealed envelopes
    

Intervention name(s): Penicillin-G-benzathine; Azithromycin
Intervention type(s): Drug; Drug
Intervention description(s): Screening examination: Medical history (emphasis on skin lesions and bone signs) Physical examination.Blood samples for VDRL and TPHA. Clinical safety. Laboratory evaluations: haemoglobin, total WBC count, differential WBC count, platelet count, ALT, AST, urea and creatinine.
Routine assessments: General clinical assessment and physical examination on Days 0 (treatment administered) and 14. Adverse events and concomitant medications (at baseline, Day 14 and in any unscheduled visit). Photograph documentation of skin lesions (at 14 days follow up visit). Follow-up visits performed on 3 and 6 will have a ± 14 days allowable window; Screening examination: Medical history (emphasis on skin lesions and bone signs) Physical examination.Blood samples for VDRL and TPHA. Clinical safety. Laboratory evaluations: haemoglobin, total WBC count, differential WBC count, platelet count, ALT, AST, urea and creatinine.
Routine assessments: General clinical assessment and physical examination on Days 0 (treatment administered) and 14. Adverse events and concomitant medications (at baseline, Day 14 and in any unscheduled visit). Photograph documentation of skin lesions (at 14 days follow up visit). Follow-up visits performed on 3 and 6 will have a ± 14 days allowable window
Other intervention name(s): Zithromax; Bicillin LA
Intervention MeSH terms: Azithromycin; Penicillins; Penicillin G; Penicillin G Benzathine; Penicillin G Procaine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Neglected diseases; Children