Buruli Ulcer Clinical Trial
Official title:
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
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.
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
- clinical evaluation, and
- by analysis of three punch biopsies (0.3 cm each) under local anaesthesia.
Only patients with confirmation of M. ulcerans disease - presence of dry reagent-based
polymerase chain reaction (DRB-PCR) signal with insertion sequence IS2404, were to be
randomised to receive either SR for 8 weeks, or 4 weeks of SR followed by oral treatment
consisting of R and clarithromycin (C), as allocated by a computer-generated program;
patients will be stratified for ulcerative or pre-ulcerative lesions.
Patients who meet the clinical criteria for M ulcerans disease but are PCR negative, will be
offered 8 weeks RS treatment, as is presently provisionally recommended by WHO, and will be
evaluated separately, according to the protocol for patients allocated to 8 weeks RS
treatment. All biopsies from lesions will be subjected to histopathology, DRB-PCR-,
microscopy, culture, genomic, sensitivity tests and external quality control in laboratories
in Kumasi (KNUST), Hamburg (BNITM), Munich (DITM) and Antwerp (ITM). Lesions will be
assessed regularly for progression or healing during treatment. Drug toxicity will likewise
be monitored: renal and audiographic tests for S and C, ECG for C, and liver enzymes for R
and C, and blood cell counts for C.
The primary endpoint is healing without recurrence at 12 months follow-up after start of
treatment Secondary endpoint is reduction in lesion surface area and/or clinically assessed
improvement on completion of treatment, averting the need for debridement surgery.
Recurrences will be biopsied for confirmation, using PCR, histopathology, and culture. In
all, 200 patients will need to be screened according to protocol, and 2x74 evaluable
patients will be randomised based on a power analysis 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 will make interim analyses.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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