Randomised Trial for Early Lesions Caused by M. Ulcerans - Comparison Between 8 Weeks Streptomycin and Rifampicin (SR), or 4 Weeks SR Followed by 4 Weeks R Plus Clarithromycin
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 151
- 试验地点
- 2
- 主要终点
- healing without recurrence and without debridement surgery at 12 months follow-up after start of treatment
研究概览
简要总结
The standard for treatment Buruli ulcer disease (BUD) used to be surgery but the WHO now advises streptomycin (S, 15 mg/kg daily, intramuscularly) and rifampicin (R,10 mg/kg daily) along with surgery. This preliminary advice was based on observations in 21 patients with pre-ulcerative lesions of BUD, who were given daily SR treatment for varying periods of time. In patients treated with SR for at least 4 weeks, M. ulcerans could no longer be cultured from excised lesions. SR has been introduced without a formal evaluation or comparison with other treatments have been conducted or published, but the impression is that this treatment is beneficial and may cure BUD without additional surgical management.
This study protocol evaluated the hypothesis that early, limited lesions of BUD(pre-ulcerative or ulcerated lesions, ≤ 10 cm maximum diameter), can be healed without recurrence using antimycobacterial drug therapy, without the need for debridement surgery.
In endemic regions in Ghana, patients will be actively recruited and followed if ≥ 5 years of age, and with early (i.e., onset < 6 months) BUD.
- consent by patients and / or care givers / legal representatives
- clinical evaluation, and by
- analysis of three 0.3 cm punch biopsies under local anaesthesia.
- disease confirmation: dry reagent-based polymerase chain reaction (DRB-PCR IS2404)
- randomization: either SR for 8 weeks, or 4 weeks of SR followed by R and clarithromycin (C)
- stratification: ulcerative or pre-ulcerative lesions.
Biopsies processed for histopathology, DRB-PCR-, microscopy, culture, genomic, and sensitivity tests. Lesions assessed regularly for progression or healing during treatment. Drug toxicity monitoring included blood cell counts, liver enzymes and renal tests; and ECG and audiographic tests.
Primary endpoint: healing without recurrence at 12 months follow-up after start of treatment Secondary endpoint: reduction in lesion surface area and/or clinically assessed improvement on completion of treatment, averting the need for debridement surgery.
Recurrences biopsied for confirmation, using PCR, histopathology, and culture. Sample size calculation: 2x74 fully evaluable patients; 80% power to detect a difference of 20 % in recurrence-free cure 12 months after start of treatment between the two groups (60 versus 80%). A Data Safety and Monitoring Board made interim analysis assessments.
详细描述
Buruli ulcer disease (BUD) is caused by infection with Mycobacterium ulcerans. It usually starts as a small nodule under the skin but may progress to an ulcerative lesion; and eventually large, usually painless ulcers may develop. When it heals - with surgery or without - it may cause severe scarring resulting in disability and deformity. BUD has emerged as an important infectious disease among rural populations in West Africa. The standard treatment used to be surgical excision for all forms and stages. In 2004. The World Health Organisation advised the use of streptomycin (S, 15 mg/kg daily, intramuscularly) and rifampicin (R,10 mg/kg daily) along with surgery. This preliminary advice was based on the observation in 21 patients with pre-ulcerative lesions of BUD, who were given daily SR treatment for varying periods of time. If patients had received such treatment for at least 4 weeks, M. ulcerans could not be cultured again from the lesions that were excised. The treatment has been implemented in areas with poor access to surgical facilities, in Pobe, Benin, and although no formal evaluation or comparison with other treatments have been conducted or published, the impression is that this treatment is probably beneficial and may cure BUD without the need for additional surgical management.
This study protocol was designed to evaluate the hypothesis that early, limited lesions of Buruli ulcer (M. ulcerans disease; pre-ulcerative or ulcerated lesions, less than or equal to 10 maximum diameter), can be healed without recurrence using antimycobacterial drug therapy, without the need for debridement surgery.
In endemic regions in Ghana, active case finding will be followed by accrual of patients
- 5 years of age and over, with
- limited early (i.e., onset less than 6 months) lesions of Buruli ulcer.
After appropriate consent by patients and / or their care givers or legal representatives, patients will be diagnosed both by
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 5 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female patients
- •At least 5 years of age
- •A clinical diagnosis of early M. ulcerans disease including:
- •Plaques and small ulcers with or without oedema and less than or equal to 10cm in maximum diameter
- •Disease duration no longer than six months
- •DRB-PCR positive for M. ulcerans
排除标准
- •Treatment with macrolide or quinolone antibiotics, or antituberculous medication, or immunomodulatory drugs including corticosteroids within the previous one month.
- •Current treatment with any drugs likely to interact with the study medication, e.g, anticoagulants, cyclosporin, phenytoin, oral contraceptive, and phenobarbitone.
- •History of hypersensitivity to rifampicin, streptomycin and or clarithromycin.
- •History or having current clinical signs of ascites, jaundice, partial or complete deafness, myasthenia gravis, renal dysfunction (known or suspected), diabetes mellitus, and immune compromise; or evidence for past or present tuberculosis.
- •Pregnancy
- •Inability to take oral medication or having gastrointestinal disease likely to interfere with drug absorption.
- •Excessive alcohol intake.
- •Any situation or condition which may compromise ability to comply with the trial procedures.
- •Lack of willingness to give informed consent (and/or assent by parent/legal representative).
研究组 & 干预措施
SR4/CR4
after 4 weeks of standard treatment with streptomycin and rifampicin, patients in the experimental arm switch to oral treatment consisting of rifampicin and clarithromycin
干预措施: SR4 - switch to CR4 (Drug)
SR8
standard treatment consisting of 8 weeks of streptomycin and rifampicin
干预措施: SR4 - switch to CR4 (Drug)
结局指标
主要结局
healing without recurrence and without debridement surgery at 12 months follow-up after start of treatment
时间窗: 12 months follow-up after start of treatment
次要结局
- reduction in lesion surface area and/or clinically assessed improvement on completion of treatment, averting the need for debridement surgery(during treatment and follow-up x 12 months)
- adverse events(during treatment and follow-up x 12 months)
- functional limitations(at end of follow-up (12 months))