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

This is a WHO-sponsored trial.

Combination therapy with streptomycin and rifampicin has been the standard antibiotic treatment for M. ulcerans infection since 2004. In March 2010, a WHO Technical Advisory Group recommended that a trial be carried out to develop a fully oral treatment for the disease. Although the current treatment is effective, injection with streptomycin is a problem. Several small observational studies (published and unpublished) have shown that a fully oral treatment is promising.

This WHO sponsored study will be a randomized, controlled open label non-inferiority phase II/III, multi-centre trial (1 centre in Benin and 4 centres in Ghana), with two parallel treatment groups. The ultimate goal is to search for an effective alternative treatment to the current standard WHO-recommended therapy for all forms of Buruli ulcer, which includes injections of streptomycin with inherent logistic, operational and safety disadvantages.

Financial and material support:

1. American Leprosy Missions, USA
2. Raoul Follereau Foundation, France
3. MAP International, USA
4. Sanofi, France
5. 7th Framework Programme of the European Union: BuruliVac project (241500)
6. Aranz Medical Limited, New Zealand

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

Eligibility Criteria:
Inclusion criteria:

* All patients (both genders) with a clinical diagnosis of BUD (categories: I and II, cross-sectional diameter ≤ 10cm) as agreed by study site treatment team led by the lead clinicians

Exclusion criteria:

1. Patients with lesion sizes \>10cm in cross-sectional diameter
2. Children \< 5 years, or \< 20 kilograms body weight
3. Pregnancy (self-reported, clinically diagnosed, or urine test (beta-hCG) positive
4. Patients with previous treatment of Buruli ulcer, tuberculosis or leprosy with at least one of the study drugs (rifampicin, streptomycin, clarithromycin)
5. Patients with history of hypersensitivity to rifampicin and/or streptomycin and/or clarithromycin
6. Patients with previous treatment with macrolide or quinolone antibiotics, or antituberculosis medication, or immuno-modulatory drugs including corticosteroids within one month
7. Patients with current treatment with any drugs likely to interact with the study medication, e.g, anticoagulants, cyclosporin, phenytoin, and phenobarbitone. Users of oral contraceptives should be notified that such contraceptive is less reliable if taken with rifampicin; alternative (mechanical) contraceptive methods will be discussed with the study participant
8. Patients with co-infection with HIV
9. Patients with history or having current clinical signs of ascites, jaundice, partial or complete deafness, myasthenia gravis, renal dysfunction (known or suspected), diabetes mellitus, and severe immune compromise (e.g., immunosuppressive drugs after organ transplant), or evidence of (previous) tuberculosis, Buruli ulcer or leprosy; or terminal illness (e.g., metastasized cancer)
10. Patients who are unable to take oral medication or having gastrointestinal disease likely to interfere with drug absorption
11. Patients with known or suspected bowel strictures who cannot tolerate macrolide antibiotics such as clarithromycin
12. Patients with mental condition, including addiction with substance abuse (alcohol, qat, etc) likely to interfere with possibility to comply with the study protocol
13. Patients who are not willing to give informed pre-consent, and consent (patient and/or parent/legal representative), or withdrawal of consent