WHO Drug Study for Buruli Ulcer - Comparison of SR8 and CR8

• healing without recurrence and without excision surgery [ Time Frame: 12 months after start of treatment ] [ Designated as safety issue: No ]
  complete epithelialisation and absence of swelling at the site of original infection, measured 12 months after start of treatment; lesion site will be examined by inspection and palpation, and documented by digital camera; digital images will be examined by panel of wound experts unaware of treatment allocation
  
  

• Recurrence rate within 12 months of treatment initiation [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  number of recurrent lesions occurring after initial healing within 12 months after start of treatment
  
  
• Rate of treatment failure within 12 months of treatment initiation [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  proportion of treatment failure will be compared between groups
  
  
• Rate of paradoxical response within 12 months of treatment initiation [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  paradoxical responses that have occurred during BUD treatment will be compared in both treatment arms
  
  
• Proportion of patients with reduction in lesion surface area within 12 months of treatment initiation [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  if not cured, will there be a difference between groups in terms of reduction of lesion size?
  
  
• Time taken for complete lesion healing within 12 months of treatment initiation [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  do lesions heal faster in one of the two treatments?
  
  
• Proportion (%) of patients with complete healing without additional surgery or relapse [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  
• Interval between healing and recurrence [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  if recurrences occur, there might be a difference in time between healing and recurrences between treatment groups
  
  
• Proportion of each type of surgery within 12 months of treatment initiation [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  We do not expect surgery but IF doctors operate, which type of surgery would doctors use, and does this differ between groups?
  
  
• Time from treatment initiation to surgery if any [ Time Frame: 12months ] [ Designated as safety issue: No ]
  does the timing of surgery differ between groups for the proportion of patients in whom doctors decide to operate?
  
  
• Proportion of patients with residual functional limitations [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  do treatments differ in terms of chance to develop functional limitations?
  
  
• Treatment discontinuation and compliance rates [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
  one treatment might be better tolerated than the other; do treatments differ in terms of adherence problems, and do participants in any of these two treatment arms differ in terms of the chance to discontinue the treatment?
  
  
• Incidence of all adverse effects (AEs) within 12 months of treatment initiation [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  adverse effects occurring during or after treatment may be different between treatments
  
  

A total of 415 patients in whom Buruli ulcer has been clinically diagnosed will be included in the study, which will consist of 332 cases of category I and II Buruli ulcers (<10 cm) confirmed by polymerase chain reaction (PCR), plus 83 non PCR-confirmed Buruli ulcers. Patients will be randomized to receive treatment with the two antibiotic regimens as follows:

(i) Regimen I (SR8): 15 mg/kg streptomycin per day intramuscular injection for 8 weeks plus 10 mg/kg per day oral rifampicin for 8 weeks; (ii) Regimen II (CR8): 15 mg/kg per day oral extended-release clarithromycin for 8 weeks plus 10 mg/kg per day oral rifampicin for 8 weeks.

Assessments before, during and after the course of antibiotic treatment will include full medical history, clinical assessments and monitoring of vital signs, assessment of the lesion, laboratory investigations, hearing test, electrocardiogram, pregnancy test, voluntary HIV counseling and testing, and functional limitation assessment. The primary efficacy parameters are healing without recurrence and without excision surgery 12 months after the start of treatment.

The primary endpoint will be assessed by a panel of experts unaware of the treatment ('single blinded' for treatment allocation).

Statistician:

Mr Bruno Scherrer, Consultant, Drugs for Neglected Diseases initiative, Switzerland

Data Management:

Mr Raymond Omollo, Drugs for Neglected Diseases initiative (DNDi) Africa