Rifampicin and clarithromycin (extended release) versus rifampicin and streptomycin for limited Buruli ulcer lesions: a randomised, open-label, non-inferiority phase 3 trial

Richard O Phillips, Jérôme Robert, Kabiru Mohamed Abass, William Thompson, Fred Stephen Sarfo, Tuah Wilson, Godfred Sarpong, Thierry Gateau, Annick Chauty, Raymond Omollo, Michael Ochieng Otieno, Thaddaeus W Egondi, Edwin O Ampadu, Didier Agossadou, Estelle Marion, Line Ganlonon, Mark Wansbrough-Jones, Jacques Grosset, John M Macdonald, Terry Treadwell, Paul Saunderson, Albert Paintsil, Linda Lehman, Michael Frimpong, Nanaa Francisca Sarpong, Raoul Saizonou, Alexandre Tiendrebeogo, Sally-Ann Ohene, Ymkje Stienstra, Kingsley B Asiedu, Tjip S van der Werf, study team, Samuel Osei Mireku, Justice Abotsi, Joseph Ken Adu Poku, Richard Asamoah-Frimpong, Bright Osei-Wusu, Edward Sarpong, Beatrice Konadu, Ernest Opoku, Mark Forson, Mathias Ndogyele, Elizabeth Ofori, Felicity Aboagye, Thomas Berko, George Amofa, Anastasia Nsiah, Joyce Mensah-Bonsu, Joseph Ofori Nyarko, Yaw Ampem Amoako, Elliot Koranteng Tannor, Justice Boakye-Appiah, Aloysius Dzibordzi Loglo, Mabel Sarpong-Duah, Bernadette Agbavor, Marie Françoise Ardent, Arnaud Yamadjako, Naomi Adanmado Gersande, Ambroise Adeye, Martial Kindjinou, Akpolan, Maxime Kiki, Espoir Sodjinou, Clémence Guegnard, Sandor-Adrian Klis, Kristien Velding, Till Omansen, David Ofori-Adjei, Sarah Eyangoh, Alan Knell, William Faber, Richard O Phillips, Jérôme Robert, Kabiru Mohamed Abass, William Thompson, Fred Stephen Sarfo, Tuah Wilson, Godfred Sarpong, Thierry Gateau, Annick Chauty, Raymond Omollo, Michael Ochieng Otieno, Thaddaeus W Egondi, Edwin O Ampadu, Didier Agossadou, Estelle Marion, Line Ganlonon, Mark Wansbrough-Jones, Jacques Grosset, John M Macdonald, Terry Treadwell, Paul Saunderson, Albert Paintsil, Linda Lehman, Michael Frimpong, Nanaa Francisca Sarpong, Raoul Saizonou, Alexandre Tiendrebeogo, Sally-Ann Ohene, Ymkje Stienstra, Kingsley B Asiedu, Tjip S van der Werf, study team, Samuel Osei Mireku, Justice Abotsi, Joseph Ken Adu Poku, Richard Asamoah-Frimpong, Bright Osei-Wusu, Edward Sarpong, Beatrice Konadu, Ernest Opoku, Mark Forson, Mathias Ndogyele, Elizabeth Ofori, Felicity Aboagye, Thomas Berko, George Amofa, Anastasia Nsiah, Joyce Mensah-Bonsu, Joseph Ofori Nyarko, Yaw Ampem Amoako, Elliot Koranteng Tannor, Justice Boakye-Appiah, Aloysius Dzibordzi Loglo, Mabel Sarpong-Duah, Bernadette Agbavor, Marie Françoise Ardent, Arnaud Yamadjako, Naomi Adanmado Gersande, Ambroise Adeye, Martial Kindjinou, Akpolan, Maxime Kiki, Espoir Sodjinou, Clémence Guegnard, Sandor-Adrian Klis, Kristien Velding, Till Omansen, David Ofori-Adjei, Sarah Eyangoh, Alan Knell, William Faber

Abstract

Background: Buruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans infection that damages the skin and subcutis. It is most prevalent in western and central Africa and Australia. Standard antimicrobial treatment with oral rifampicin 10 mg/kg plus intramuscular streptomycin 15 mg/kg once daily for 8 weeks (RS8) is highly effective, but streptomycin injections are painful and potentially harmful. We aimed to compare the efficacy and tolerability of fully oral rifampicin 10 mg/kg plus clarithromycin 15 mg/kg extended release once daily for 8 weeks (RC8) with that of RS8 for treatment of early Buruli ulcer lesions.

Methods: We did an open-label, non-inferiority, randomised (1:1 with blocks of six), multicentre, phase 3 clinical trial comparing fully oral RC8 with RS8 in patients with early, limited Buruli ulcer lesions. There were four trial sites in hospitals in Ghana (Agogo, Tepa, Nkawie, Dunkwa) and one in Benin (Pobè). Participants were included if they were aged 5 years or older and had typical Buruli ulcer with no more than one lesion (caterories I and II) no larger than 10 cm in diameter. The trial was open label, and neither the investigators who took measurements of the lesions nor the attending doctors were masked to treatment assignment. The primary clinical endpoint was lesion healing (ie, full epithelialisation or stable scar) without recurrence at 52 weeks after start of antimicrobial therapy. The primary endpoint and safety were assessed in the intention-to-treat population. A sample size of 332 participants was calculated to detect inferiority of RC8 by a margin of 12%. This study was registered with ClinicalTrials.gov, NCT01659437.

Findings: Between Jan 1, 2013, and Dec 31, 2017, participants were recruited to the trial. We stopped recruitment after 310 participants. Median age of participants was 14 years (IQR 10-29) and 153 (52%) were female. 297 patients had PCR-confirmed Buruli ulcer; 151 (51%) were assigned to RS8 treatment, and 146 (49%) received oral RC8 treatment. In the RS8 group, lesions healed in 144 (95%, 95% CI 91 to 98) of 151 patients, whereas lesions healed in 140 (96%, 91 to 99) of 146 patients in the RC8 group. The difference in proportion, -0·5% (-5·2 to 4·2), was not significantly greater than zero (p=0·59), showing that RC8 treatment is non-inferior to RS8 treatment for lesion healing at 52 weeks. Treatment-related adverse events were recorded in 20 (13%) patients receiving RS8 and in nine (7%) patients receiving RC8. Most adverse events were grade 1-2, but one (1%) patient receiving RS8 developed serious ototoxicity and ended treatment after 6 weeks. No patients needed surgical resection. Four patients (two in each study group) had skin grafts.

Interpretation: Fully oral RC8 regimen was non-inferior to RS8 for treatment of early, limited Buruli ulcer and was associated with fewer adverse events. Therefore, we propose that fully oral RC8 should be the preferred therapy for early, limited lesions of Buruli ulcer.

Funding: WHO with additional support from MAP International, American Leprosy Missions, Fondation Raoul Follereau France, Buruli ulcer Groningen Foundation, Sanofi-Pasteur, and BuruliVac.

© 2020 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.

Figures

Figure 1
Figure 1
Trial profile
Figure 2
Figure 2
Cumulative probability of a Buruli ulcer lesion healing over time 95% CIs are shown. Lesion healing was defined by full epithelialisation or stable scar. HR=hazard ratio. RC8=oral rifampicin 10 mg/kg plus clarithromycin 15 mg/kg extended release once daily for 8 weeks. RS8=oral rifampicin 10 mg/kg plus intramuscular streptomycin 15 mg/kg once daily for 8 weeks.

References

    1. WHO Neglected tropical diseases. 2020. (accessed Sept 17, 2019).
    1. WHO Buruli ulcer. 2020. (accessed Sept 17, 2019).
    1. WHO . Fourth WHO report in neglected tropical disease; integrating NTD into global health and development. World Health Organization; Geneva: 2017.
    1. Simpson H, Deribe K, Tabah EN. Mapping the global distribution of Buruli ulcer: a systematic review with evidence consensus. Lancet Glob Health. 2019;7:e912–e922.
    1. Johnson PDR. Buruli ulcer: here today but where tomorrow? Lancet Glob Health. 2019;7:e821–e822.
    1. Yeboah-Manu D, Aboagye SY, Asare P. Laboratory confirmation of Buruli ulcer cases in Ghana, 2008–2016. PLoS Negl Trop Dis. 2018;12
    1. Beeres DT, Horstman J, van der Tak P. The paediatric participation scale measuring participation restrictions among former Buruli ulcer patients under the age of 15 in Ghana and Benin: development and first validation results. PLoS Negl Trop Dis. 2019;13
    1. Tai AYC, Athan E, Friedman ND, Hughes A, Walton A, O’Brien DP. Increased severity and spread of Mycobacterium ulcerans, southeastern Australia. Emerg Infect Dis. 2018;24:58–64.
    1. Loftus MJ, Tay E-L, Globan M. Epidemiology of Buruli ulcer infections, Victoria, Australia, 2011–2016. Emerg Infect Dis. 2018;24:1988–1997.
    1. Etuaful S, Carbonnelle B, Grosset J. Efficacy of the combination rifampin-streptomycin in preventing growth of Mycobacterium ulcerans in early lesions of Buruli ulcer in humans. Antimicrob Agents Chemother. 2005;49:3182–3186.
    1. Stienstra Y, van der Graaf WTA, Asamoa K, van der Werf TS. Beliefs and attitudes toward Buruli ulcer in Ghana. Am J Trop Med Hyg. 2002;67:207–213.
    1. Stienstra Y, van Roest MHG, van Wezel MJ. Factors associated with functional limitations and subsequent employment or schooling in Buruli ulcer patients. Trop Med Int Health. 2005;10:1251–1257.
    1. Vincent QB, Ardant M-F, Adeye A. Clinical epidemiology of laboratory-confirmed Buruli ulcer in Benin: a cohort study. Lancet Glob Health. 2014;2:e422–e430.
    1. Sarfo FS, Phillips R, Asiedu K. Clinical efficacy of combination of rifampin and streptomycin for treatment of Mycobacterium ulcerans disease. Antimicrob Agents Chemother. 2010;54:3678–3685.
    1. Nienhuis WA, Stienstra Y, Thompson WA. Antimicrobial treatment for early, limited Mycobacterium ulcerans infection: a randomised controlled trial. Lancet. 2010;375:664–672.
    1. Klis S, Stienstra Y, Phillips RO, Abass KM, Tuah W, van der Werf TS. Long term streptomycin toxicity in the treatment of Buruli ulcer: follow-up of participants in the BURULICO drug trial. PLoS Negl Trop Dis. 2014;8
    1. Ji B, Chauffour A, Robert J, Lefrançois S, Jarlier V. Orally administered combined regimens for treatment of Mycobacterium ulcerans infection in mice. Antimicrob Agents Chemother. 2007;51:3737–3739.
    1. Almeida D, Converse PJ, Ahmad Z, Dooley KE, Nuermberger EL, Grosset JH. Activities of rifampin, rifapentine and clarithromycin alone and in combination against Mycobacterium ulcerans disease in mice. PLoS Negl Trop Dis. 2011;5
    1. Phillips RO, Sarfo FS, Abass MK. Clinical and bacteriological efficacy of rifampin-streptomycin combination for two weeks followed by rifampin and clarithromycin for six weeks for treatment of Mycobacterium ulcerans disease. Antimicrob Agents Chemother. 2014;58:1161–1166.
    1. Chauty A, Ardant M-F, Marsollier L. Oral treatment for Mycobacterium ulcerans infection: results from a pilot study in Benin. Clin Infect Dis. 2011;52:94–96.
    1. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. PLoS Med. 2010;7
    1. WHO Facilities involved in Buruli ulcer clinical trial 2012–2015 in Ghana and Benin. 2012.
    1. Abass KM, van der Werf TS, Phillips RO. Buruli ulcer control in a highly endemic district in Ghana: role of community-based surveillance volunteers. Am J Trop Med Hyg. 2015;92:115–117.
    1. Barogui YT, Sopoh GE, Johnson RC. Contribution of the community health volunteers in the control of Buruli ulcer in Bénin. PLoS Negl Trop Dis. 2014;8
    1. Herbinger K-H, Adjei O, Awua-Boateng N-Y. Comparative study of the sensitivity of different diagnostic methods for the laboratory diagnosis of Buruli ulcer disease. Clin Infect Dis. 2009;48:1055–1064.
    1. Eddyani M, Lavender C, de Rijk WB. Multicenter external quality assessment program for PCR detection of Mycobacterium ulcerans in clinical and environmental specimens. PLoS One. 2014;9
    1. Nienhuis WA, Stienstra Y, Abass KM. Paradoxical responses after start of antimicrobial treatment in Mycobacterium ulcerans infection. Clin Infect Dis. 2012;54:519–526.
    1. Velink A, Woolley RJ, Phillips RO. Former buruli ulcer patients’ experiences and wishes may serve as a guide to further improve buruli ulcer management. PLoS Negl Trop Dis. 2016;10
    1. Ampah KA, Asare P, Binnah DD-G. Burden and historical trend of buruli ulcer prevalence in selected communities along the Offin River of Ghana. PLoS Negl Trop Dis. 2016;10
    1. Anagonou EG, Johnson RC, Barogui YT. Decrease in Mycobacterium ulcerans disease (Buruli ulcer) in the Lalo District of Bénin (west Africa) BMC Infect Dis. 2019;19:247.
    1. Wadagni AC, Barogui YT, Johnson RC. Delayed versus standard assessment for excision surgery in patients with Buruli ulcer in Benin: a randomised controlled trial. Lancet Infect Dis. 2018;18:650–656.
    1. Friedman ND, Athan E, Walton AL, O’Brien DP. Increasing experience with primary oral medical therapy for Mycobacterium ulcerans disease in an Australian cohort. Antimicrob Agents Chemother. 2016;60:2692–2695.
    1. O’Brien DP, Friedman D, Hughes A, Walton A, Athan E. Antibiotic complications during the treatment of Mycobacterium ulcerans disease in Australian patients. Intern Med J. 2017;47:1011–1019.
    1. Klis S, Kingma RA, Tuah W, van der Werf TS, Stienstra Y. Clinical outcomes of Ghanaian Buruli ulcer patients who defaulted from antimicrobial therapy. Trop Med Int Health. 2016;21:1191–1196.
    1. O’Brien DP, Friedman ND, Cowan R, Walton A, Athan E. Six versus eight weeks of antibiotics for small Mycobacterium ulcerans lesions in Australian patients. Clin Infect Dis. 2019 doi: 10.1093/cid/ciz532. published online June 20.
    1. Alffenaar JWC, Nienhuis WA, de Velde F. Pharmacokinetics of rifampin and clarithromycin in patients treated for Mycobacterium ulcerans infection. Antimicrob Agents Chemother. 2010;54:3878–3883.
    1. Marsollier L, Honoré N, Legras P. Isolation of three Mycobacterium ulcerans strains resistant to rifampin after experimental chemotherapy of mice. Antimicrob Agents Chemother. 2003;47:1228–1232.
    1. Jansson M, Beissner M, Phillips RO. Comparison of two assays for molecular determination of rifampin resistance in clinical samples from patients with Buruli ulcer disease. J Clin Microbiol. 2014;52:1246–1249.
    1. Converse PJ, Almeida DV, Tasneen R. 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;12
    1. Converse PJ, Almeida DV, Tyagi S, Xu J, Nuermberger EL. Shortening buruli ulcer treatment with combination therapy targeting the respiratory chain and exploiting Mycobacterium ulcerans gene decay. Antimicrob Agents Chemother. 2019;63:e00426–e00519.
    1. Scherr N, Bieri R, Thomas SS. Targeting the Mycobacterium ulcerans cytochrome bc1:aa3 for the treatment of Buruli ulcer. Nat Commun. 2018;9:5370–5379.

Source: PubMed

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