BURULICO Drug Trial Study Protocol: RCT SR8/SR4+CR4, GHANA

Summary

The standard for treatment Buruli ulcer disease (BUD) used to be surgery but the WHO now advises streptomycin (S, 15 mg/kg daily, intramuscularly) and rifampicin (R,10 mg/kg daily) along with surgery. This preliminary advice was based on observations in 21 patients with pre-ulcerative lesions of BUD, who were given daily SR treatment for varying periods of time. In patients treated with SR for at least 4 weeks, M. ulcerans could no longer be cultured from excised lesions. SR has been introduced without a formal evaluation or comparison with other treatments have been conducted or published, but the impression is that this treatment is beneficial and may cure BUD without additional surgical management. This study protocol evaluated the hypothesis that early, limited lesions of BUD(pre-ulcerative or ulcerated lesions, ≤ 10 cm maximum diameter), can be healed without recurrence using antimycobacterial drug therapy, without the need for debridement surgery. In endemic regions in Ghana, patients will be actively recruited and followed if ≥ 5 years of age, and with early (i.e., onset \< 6 months) BUD. * consent by patients and / or care givers / legal representatives * clinical evaluation, and by * analysis of three 0.3 cm punch biopsies under local anaesthesia. * disease confirmation: dry reagent-based polymerase chain reaction (DRB-PCR IS2404) * randomization: either SR for 8 weeks, or 4 weeks of SR followed by R and clarithromycin (C) * stratification: ulcerative or pre-ulcerative lesions. Biopsies processed for histopathology, DRB-PCR-, microscopy, culture, genomic, and sensitivity tests. Lesions assessed regularly for progression or healing during treatment. Drug toxicity monitoring included blood cell counts, liver enzymes and renal tests; and ECG and audiographic tests. Primary endpoint: healing without recurrence at 12 months follow-up after start of treatment Secondary endpoint: reduction in lesion surface area and/or clinically assessed improvement on completion of treatment, averting the need for debridement surgery. Recurrences biopsied for confirmation, using PCR, histopathology, and culture. Sample size calculation: 2x74 fully evaluable patients; 80% power to detect a difference of 20 % in recurrence-free cure 12 months after start of treatment between the two groups (60 versus 80%). A Data Safety and Monitoring Board made interim analysis assessments.

Timeline

Start

2006-05

Primary completion

2008-01

Completion

2009-02

Publications

• Background van der Werf TS, Stienstra Y, Johnson RC, Phillips R, Adjei O, Fleischer B, Wansbrough-Jones MH, Johnson PD, Portaels F, van der Graaf WT, Asiedu K. Mycobacterium ulcerans disease. Bull World Health Organ. 2005 Oct;83(10):785-91. Epub 2005 Nov 10.
• Background van der Werf TS, van der Graaf WT, Tappero JW, Asiedu K. Mycobacterium ulcerans infection. Lancet. 1999 Sep 18;354(9183):1013-8. doi: 10.1016/S0140-6736(99)01156-3.
• Background Etuaful S, Carbonnelle B, Grosset J, Lucas S, Horsfield C, Phillips R, Evans M, Ofori-Adjei D, Klustse E, Owusu-Boateng J, Amedofu GK, Awuah P, Ampadu E, Amofah G, Asiedu K, Wansbrough-Jones M. Efficacy of the combination rifampin-streptomycin in preventing growth of Mycobacterium ulcerans in early lesions of Buruli ulcer in humans. Antimicrob Agents Chemother. 2005 Aug;49(8):3182-6. doi: 10.1128/AAC.49.8.3182-3186.2005.
• Barogui YT, Klis SA, Johnson RC, Phillips RO, van der Veer E, van Diemen C, van der Werf TS, Stienstra Y. Genetic Susceptibility and Predictors of Paradoxical Reactions in Buruli Ulcer. PLoS Negl Trop Dis. 2016 Apr 20;10(4):e0004594. doi: 10.1371/journal.pntd.0004594. eCollection 2016 Apr.
• Nienhuis WA, Stienstra Y, Abass KM, Tuah W, Thompson WA, Awuah PC, Awuah-Boateng NY, Adjei O, Bretzel G, Schouten JP, van der Werf TS. Paradoxical responses after start of antimicrobial treatment in Mycobacterium ulcerans infection. Clin Infect Dis. 2012 Feb 15;54(4):519-26. doi: 10.1093/cid/cir856. Epub 2011 Dec 7.
• 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.

Drugs

Indications