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

Study Overview
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Brief Summary
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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 Several small observational studies (published and unpublished) have shown that a fully oral treatment is promising.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: American Leprosy Missions, USA Raoul Follereau Foundation, France MAP International, USA Sanofi, France 7th Framework Programme of the European Union: BuruliVac project (241500) Aranz Medical Limited, New Zealand

Detailed Description
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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

Official Title
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Randomized Controlled Trial Comparing Efficacy of 8 Weeks Treatment With Clarithromycin and Rifampicin Versus Streptomycin and Rifampicin for Buruli Ulcer (M. Ulcerans Infection)

Conditions
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Mycobacterium Ulcerans Infection

Intervention / Treatment
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* Drug: Clarithromycin Extended Release
* Drug: Streptomycin intramuscular injection


Participation Criteria
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Eligibility Criteria
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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: Patients with lesion sizes >10cm in cross-sectional diameter Children < 5 years, or < 20 kilograms body weight Pregnancy (self-reported, clinically diagnosed, or urine test (beta-hCG) positive Patients with previous treatment of Buruli ulcer, tuberculosis or leprosy with at least one of the study drugs (rifampicin, streptomycin, clarithromycin) Patients with history of hypersensitivity to rifampicin and/or streptomycin and/or clarithromycin Patients with previous treatment with macrolide or quinolone antibiotics, or antituberculosis medication, or immuno-modulatory drugs including corticosteroids within one month 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 Patients with co-infection with HIV 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) Patients who are unable to take oral medication or having gastrointestinal disease likely to interfere with drug absorption Patients with known or suspected bowel strictures who cannot tolerate macrolide antibiotics such as clarithromycin Patients with mental condition, including addiction with substance abuse (alcohol, qat, etc) likely to interfere with possibility to comply with the study protocol Patients who are not willing to give informed pre-consent, and consent (patient and/or parent/legal representative), or withdrawal of consent

Ages Eligible for Study
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Minimum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: SR8<br>Streptomycin (S: 15 mg/kg per day, intramuscularly) in combination with rifampicin (R: 10 mg/kg per day, orally) for 8 weeks | Drug: Streptomycin intramuscular injection<br>* daily intramuscular drug injection<br>|
| Experimental: CR8<br>Clarithromycin (C: 15 mg/kg per day, oral extended release formulation) in combination with rifampicin (10 mg/kg per day, orally) for 8 weeks | Drug: Clarithromycin Extended Release<br>* oral administration of Clarithromycin extended release<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| healing without recurrence and without excision surgery | 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 | 12 months after start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence rate within 12 months of treatment initiation | number of recurrent lesions occurring after initial healing within 12 months after start of treatment | 12 months | 
| Rate of treatment failure within 12 months of treatment initiation | proportion of treatment failure will be compared between groups | 12 months | 
| Rate of paradoxical response within 12 months of treatment initiation | paradoxical responses that have occurred during BUD treatment will be compared in both treatment arms | 12 months | 
| Proportion of patients with reduction in lesion surface area within 12 months of treatment initiation | if not cured, will there be a difference between groups in terms of reduction of lesion size? | 12 months | 
| Time taken for complete lesion healing within 12 months of treatment initiation | do lesions heal faster in one of the two treatments? | 12 months | 
| Proportion (%) of patients with complete healing without additional surgery or relapse |  | 12 months | 
| Interval between healing and recurrence | if recurrences occur, there might be a difference in time between healing and recurrences between treatment groups | 12 months | 
| Proportion of each type of surgery within 12 months of treatment initiation | We do not expect surgery but IF doctors operate, which type of surgery would doctors use, and does this differ between groups? | 12 months | 
| Time from treatment initiation to surgery if any | does the timing of surgery differ between groups for the proportion of patients in whom doctors decide to operate? | 12months | 
| Proportion of patients with residual functional limitations | do treatments differ in terms of chance to develop functional limitations? | 12 months | 
| Treatment discontinuation and compliance rates | 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? | 8 weeks | 
| Incidence of all adverse effects (AEs) within 12 months of treatment initiation | adverse effects occurring during or after treatment may be different between treatments | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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M. ulcerans, Buruli ulcer, drug trial, clarithromycin