Clinical trial NCT01659437: WHO Drug Study for Buruli Ulcer - Comparison of SR8 and CR8
Official title: Randomized Controlled Trial Comparing Efficacy of 8 Weeks Treatment With Clarithromycin and Rifampicin Versus Streptomycin and Rifampicin for Buruli Ulcer (M. Ulcerans Infection)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Mycobacterium Ulcerans Infection
Keywords: M. ulcerans
Buruli ulcer
drug trial
clarithromycin
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
Collaborators: name: University of Groningen
name: Faculté de Médecine P&M Curie, Paris-6 - Site Pitié-Salpêtrière, France
name: Drugs for Neglected Diseases
name: World Alliance for Wound and Lymphoedema Care, Switzerland
name: Inserm U892/CNRS 699 bactériologie, Université CHU;Angers- IRIS France
name: Institute of Tropical Medicine, Antwerp, Belgium
name: National Buruli ulcer Control Programme, Ghana Health Service, Accra, Ghana
name: School of Med Sciences, Kwame Nkrumah Univ of Sci & Techn, Kumasi, Ghana
name: Komfo Anokye Teaching Hospital
name: Kumasi Center for Collaborative Research into Tropical Medicine, Kumasi, Ghana
name: Plastic Surgery and Burns Centre, Korle-Bu Teaching Hospital, Accra, Ghana
name: University of Ghana
name: Noguchi Memorial Institute of Medical Research, Accra, Ghana
name: Program Nat de Lutte contre la Lèpre et l'UB;Ulcère de Buruli, Cotonou, Benin
First posted: 2012-08-07
Enrollment: 310
Sex: ALL
Minimum age (years): 5
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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 Several small observational studies (published and unpublished) have shown that a fully oral treatment is promising.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

Detailed description: 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

Primary outcomes:
measure: healing without recurrence and without excision surgery
timeFrame: 12 months after start of treatment
Secondary outcomes:
measure: Recurrence rate within 12 months of treatment initiation
timeFrame: 12 months
measure: Rate of treatment failure within 12 months of treatment initiation
timeFrame: 12 months
measure: Rate of paradoxical response within 12 months of treatment initiation
timeFrame: 12 months
measure: Proportion of patients with reduction in lesion surface area within 12 months of treatment initiation
timeFrame: 12 months
measure: Time taken for complete lesion healing within 12 months of treatment initiation
timeFrame: 12 months
measure: Proportion (%) of patients with complete healing without additional surgery or relapse
timeFrame: 12 months
measure: Interval between healing and recurrence
timeFrame: 12 months
measure: Proportion of each type of surgery within 12 months of treatment initiation
timeFrame: 12 months
measure: Time from treatment initiation to surgery if any
timeFrame: 12months
measure: Proportion of patients with residual functional limitations
timeFrame: 12 months
measure: Treatment discontinuation and compliance rates
timeFrame: 8 weeks
measure: Incidence of all adverse effects (AEs) within 12 months of treatment initiation
timeFrame: 12 months
Other outcomes:
Locations:
city: Pobè
country: Benin
facility: Pobè Treatment Center
city: Agogo
country: Ghana
facility: Agogo Presbyterian Hospital
city: Dunkwa
country: Ghana
facility: Dunkwa Government Hospital
city: Nkawie Panyin
country: Ghana
facility: Nkawie-Toase Government Hospital
city: Tepa
country: Ghana
facility: Tepa Government Hosital
Study officials:
affiliation: University of Groningen, University Medical Centre Groningen
name: Tjip S van der Werf, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Komfo Anokye Teaching Hospital, Kwame Nkrumah University of Science & Technology, Kumasi, Ghana
name: Richard O Phillips, MD, PhD
role: STUDY_DIRECTOR
affiliation: Pobè Health Centre, Pobè, Bénin
name: Annick Chauty, MD
role: STUDY_DIRECTOR
affiliation: WHO, GBUI, Geneva, Switserland
name: Kingsley B Asiedu, MD, MPH
role: STUDY_CHAIR
References:
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