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| Name | Class |
|---|---|
| University of Groningen | OTHER |
| Pitié-Salpêtrière Hospital | OTHER |
| Drugs for Neglected Diseases | OTHER |
| World Alliance for Wound and Lymphoedema Care, Switzerland |
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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 Several small observational studies (published and unpublished) have shown that a fully oral treatment is promising.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:
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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| SR8 | Active Comparator | Streptomycin (S: 15 mg/kg per day, intramuscularly) in combination with rifampicin (R: 10 mg/kg per day, orally) for 8 weeks |
|
| CR8 | Experimental | Clarithromycin (C: 15 mg/kg per day, oral extended release formulation) in combination with rifampicin (10 mg/kg per day, orally) for 8 weeks |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Clarithromycin Extended Release | Drug | oral administration of Clarithromycin extended release |
| |
| 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 |
| 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 |
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Inclusion criteria:
Exclusion criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Tjip S van der Werf, MD, PhD | University of Groningen, University Medical Centre Groningen | Principal Investigator |
| Richard O Phillips, MD, PhD | Komfo Anokye Teaching Hospital, Kwame Nkrumah University of Science & Technology, Kumasi, Ghana | Study Director |
| Annick Chauty, MD | Pobè Health Centre, Pobè, Bénin | Study Director |
| Kingsley B Asiedu, MD, MPH | WHO, GBUI, Geneva, Switserland | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Pobè Treatment Center | Pobè | Benin | ||||
| Agogo Presbyterian Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20137805 | Background | Nienhuis WA, Stienstra Y, Thompson WA, Awuah PC, Abass KM, Tuah W, Awua-Boateng NY, Ampadu EO, Siegmund V, Schouten JP, Adjei O, Bretzel G, van der Werf TS. Antimicrobial treatment for early, limited Mycobacterium ulcerans infection: a randomised controlled trial. Lancet. 2010 Feb 20;375(9715):664-72. doi: 10.1016/S0140-6736(09)61962-0. Epub 2010 Feb 3. | |
| 21148526 |
| Label | URL |
|---|---|
| WHO Buruli ulcer website | View source |
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after publication, IPD will be made available at the time of publication; enrollment is complewted with 310 participants enrolled by Dec 2017; final report submitted for publication Sept 2019
data analysis report as well as data in OpenClinica deposited with DNDi Regional Africa Office Nairobi
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| ID | Term |
|---|---|
| D054312 | Buruli Ulcer |
| ID | Term |
|---|---|
| D009165 | Mycobacterium Infections, Nontuberculous |
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
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| UNKNOWN |
| University Hospital, Angers | OTHER_GOV |
| Institute of Tropical Medicine, Antwerp, Belgium | UNKNOWN |
| National Buruli ulcer Control Programme, Ghana Health Service, Accra, Ghana | UNKNOWN |
| School of Med Sciences, Kwame Nkrumah Univ of Sci & Techn, Kumasi, Ghana | UNKNOWN |
| Komfo Anokye Teaching Hospital | OTHER |
| Kumasi Center for Collaborative Research into Tropical Medicine, Kumasi, Ghana | UNKNOWN |
| Plastic Surgery and Burns Centre, Korle-Bu Teaching Hospital, Accra, Ghana | UNKNOWN |
| University of Ghana | OTHER |
| Noguchi Memorial Institute of Medical Research, Accra, Ghana | UNKNOWN |
| Program Nat de Lutte contre la Lèpre et l'UB;Ulcère de Buruli, Cotonou, Benin | UNKNOWN |
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| Streptomycin intramuscular injection |
| Drug |
daily intramuscular drug injection |
|
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 |
| Agogo |
| Ghana |
| Dunkwa Government Hospital | Dunkwa-on-Offin | Ghana |
| Nkawie-Toase Government Hospital | Nkawie Panyin | Ghana |
| Tepa Government Hosital | Tepa | Ghana |
| Chauty A, Ardant MF, Marsollier L, Pluschke G, Landier J, Adeye A, Goundote A, Cottin J, Ladikpo T, Ruf T, Ji B. Oral treatment for Mycobacterium ulcerans infection: results from a pilot study in Benin. Clin Infect Dis. 2011 Jan 1;52(1):94-6. doi: 10.1093/cid/ciq072. |
| 21152060 | Background | Gordon CL, Buntine JA, Hayman JA, Lavender CJ, Fyfe JA, Hosking P, Starr M, Johnson PD. All-oral antibiotic treatment for buruli ulcer: a report of four patients. PLoS Negl Trop Dis. 2010 Nov 30;4(11):e770. doi: 10.1371/journal.pntd.0000770. No abstract available. |
| 22272368 | Background | O'Brien DP, McDonald A, Callan P, Robson M, Friedman ND, Hughes A, Holten I, Walton A, Athan E. Successful outcomes with oral fluoroquinolones combined with rifampicin in the treatment of Mycobacterium ulcerans: an observational cohort study. PLoS Negl Trop Dis. 2012 Jan;6(1):e1473. doi: 10.1371/journal.pntd.0001473. Epub 2012 Jan 17. |
| 32171422 | Derived | Phillips RO, Robert J, Abass KM, Thompson W, Sarfo FS, Wilson T, Sarpong G, Gateau T, Chauty A, Omollo R, Ochieng Otieno M, Egondi TW, Ampadu EO, Agossadou D, Marion E, Ganlonon L, Wansbrough-Jones M, Grosset J, Macdonald JM, Treadwell T, Saunderson P, Paintsil A, Lehman L, Frimpong M, Sarpong NF, Saizonou R, Tiendrebeogo A, Ohene SA, Stienstra Y, Asiedu KB, van der Werf TS; study team. Rifampicin and clarithromycin (extended release) versus rifampicin and streptomycin for limited Buruli ulcer lesions: a randomised, open-label, non-inferiority phase 3 trial. Lancet. 2020 Apr 18;395(10232):1259-1267. doi: 10.1016/S0140-6736(20)30047-7. Epub 2020 Mar 12. |
| 30102705 | Derived | Converse PJ, Almeida DV, Tasneen R, Saini V, Tyagi S, Ammerman NC, Li SY, Anders NM, Rudek MA, Grosset JH, Nuermberger EL. Shorter-course treatment for Mycobacterium ulcerans disease with high-dose rifamycins and clofazimine in a mouse model of Buruli ulcer. PLoS Negl Trop Dis. 2018 Aug 13;12(8):e0006728. doi: 10.1371/journal.pntd.0006728. eCollection 2018 Aug. |
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| D012883 | Skin Ulcer |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |