Single-dose Azithromycin for the Treatment of Yaws

Yaws Clinical Trial

Official title:

Single-dose Azithromycin Versus Penicillin G Benzathine for the Treatment of Yaws in Children

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01382004
• Other study ID #: YAWS-AZ01
• Status: Completed
• Phase: Phase 3
• First received: June 23, 2011
• Last updated: April 11, 2012
• Start date: September 2010
• Est. completion date: September 2011

Study information

• Verified date: April 2012
• Source: Lihir Medical Centre
• Contact: n/a
• Is FDA regulated: No
• Health authority: Papua New Guinea: Medical Society of Papua New Guinea
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 255
• Est. completion date: September 2011
• Est. primary completion date: September 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 6 Months to 15 Years

Eligibility

Inclusion Criteria:

• All children 6 months to 15 years of age who present to LMC with suggestive skin lesions or joint pains and VDRL and TPHA testing are positive

• Suggestive skin lesions defined as: Symptomatic > 4 weeks, painless, a traumatic ulcers with raised margins. VDRL positive when titer of at least 1:16

Exclusion Criteria:

• Pregnancy

• Less than 6 months of age

• Known allergy to penicillin or macrolide

• Use of antibiotics active against treponema during the preceding six months (penicillin-G-benzathine, ceftriaxone, azithromycin or doxycycline)

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Neglected Tropical Disease
• Treponema Infection
• Yaws

Intervention

Drug:
• Penicillin-G-benzathine
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
• Azithromycin
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

Locations

Country	Name	City	State
Papua New Guinea	Lihir Medical Centre	Kavieng	New Ireland Province

Sponsors (2)

Lead Sponsor	Collaborator
Lihir Medical Centre	Centre For International Health

Country where clinical trial is conducted

Papua New Guinea, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Serologic cure	Serologic cure, defined as a decrease in the VDRL titer by at least two dilutions at six month follow-up examination, with the titer at the time of treatment used as the baseline.; In the case of primary skin lesions, complete resolution or improvement of lesions within two weeks after treatment is also required.	6 months follow up	No
Secondary	clinical cure	Clinical cure (improvement 14 days after treatment, assessed by photograph comparison over the time)	6 months	No
Secondary	3 months cure rate	Serological Cure rates three months after treatment	3 months	No