Mycobacterium Ulcerans Infection Clinical Trial
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)
| Verified date | September 2019 |
| Source | University Medical Center Groningen |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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Several small observational studies (published and unpublished) have shown that a fully oral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
| Status | Completed |
| Enrollment | 310 |
| Est. completion date | January 2018 |
| Est. primary completion date | December 2017 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 5 Years and older |
| Eligibility |
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 |
| Country | Name | City | State |
|---|---|---|---|
| Benin | Pobè Treatment Center | Pobè | |
| Ghana | Agogo Presbyterian Hospital | Agogo | |
| Ghana | Dunkwa Government Hospital | Dunkwa | |
| Ghana | Nkawie-Toase Government Hospital | Nkawie Panyin | |
| Ghana | Tepa Government Hosital | Tepa |
| Lead Sponsor | Collaborator |
|---|---|
| University Medical Center Groningen | Drugs for Neglected Diseases, Faculté de Médecine P&M Curie, Paris-6 - Site Pitié-Salpêtrière, France, Inserm U892/CNRS 699 bactériologie, Université CHU;Angers- IRIS France, Institute of Tropical Medicine, Antwerp, Belgium, Komfo Anokye Teaching Hospital, Kumasi Center for Collaborative Research into Tropical Medicine, Kumasi, Ghana, National Buruli ulcer Control Programme, Ghana Health Service, Accra, Ghana, Noguchi Memorial Institute of Medical Research, Accra, Ghana, Plastic Surgery and Burns Centre, Korle-Bu Teaching Hospital, Accra, Ghana, Program Nat de Lutte contre la Lèpre et l'UB;Ulcère de Buruli, Cotonou, Benin, School of Med Sciences, Kwame Nkrumah Univ of Sci & Techn, Kumasi, Ghana, University of Ghana, University of Groningen, World Alliance for Wound and Lymphoedema Care, Switzerland |
Benin, Ghana,
Chauty A, Ardant MF, Marsollier L, Pluschke G, Landier J, Adeye A, Goundoté 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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | 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 | 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 | |
| Secondary | Rate of treatment failure within 12 months of treatment initiation | proportion of treatment failure will be compared between groups | 12 months | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | Time taken for complete lesion healing within 12 months of treatment initiation | do lesions heal faster in one of the two treatments? | 12 months | |
| Secondary | Proportion (%) of patients with complete healing without additional surgery or relapse | 12 months | ||
| Secondary | Interval between healing and recurrence | if recurrences occur, there might be a difference in time between healing and recurrences between treatment groups | 12 months | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | Proportion of patients with residual functional limitations | do treatments differ in terms of chance to develop functional limitations? | 12 months | |
| Secondary | 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 | |
| Secondary | 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 |