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Randomised Trial to Compare Clarithromycin (Extended Release)-Rifampicin and Streptomycin-Rifampicin for Early, Limited Lesions of <i>M. Ulcerans</i> Infection

2019; RELX Group (Netherlands); Linguagem: Inglês

10.2139/ssrn.3458507

1556-5068

Richard Odame Phillips, J. Robert, Kabiru Mohamed Abass, William A. Thompson, Fred Stephen Sarfo, Wilson Tuah, Godfred Sarpong, Thierry Gateau, Annick Chauty, Raymond Omollo, Michael Ochieng Otieno, Thaddaeus Egondi, Edwin Ampadu, Didier Agossadou, Estelle Marion, Line Ganlonon, Mark Wansbrough‐Jones, J Grosset, John M. MacDonald, Terry Treadwell, Paul Saunderson, Albert Paintsil, Linda Lehman, Michael Frimpong, Francisca Nanaa Sarpong, Raoul Saizonou, Alexandre Tiendrébéogo, Sally-Ann Ohene, Ymkje Stienstra, Kingsley Asiedu, Tjip S. van der Werf, Buruli Ulcer Clinical Trial Study Team,

Infectious Diseases and Mycology

Background: Buruli ulcer (Mycobacterium ulcerans infection) is a Neglected Tropical Disease characterised by severe subcutaneous necrosis, with occasional bone involvement. Being reported from 33 countries, it is most prevalent in West and Central Africa, and Australia. In Africa, the major burden is borne by poor rural children. If left untreated, Buruli ulcer may progress to cause severe suffering and ultimately stigmatising disability resulting in school drop-out and loss of income. Standard antimicrobial treatment with oral rifampicin 10 mg/kg and intramuscular streptomycin 15 mg/kg for eight weeks (RS8) is highly effective but streptomycin injections are painful and may cause hearing loss.Methods: Between January 2013 and December 2017, we conducted an open label randomised multicentre phase III clinical trial with non-inferiority design comparing fully oral treatment with rifampicin and clarithromycin 15 mg/kg extended release (RC8) with RS8. A sample size of 332 participants was calculated to detect inferiority of CR8 by a margin of 12%.Findings: We stopped recruitment after 310 participants, 297 of whom had PCR-confirmed Buruli ulcer; 151 were assigned to SR8 treatment, while 146 received oral CR8 treatment. In the RS8 arm, 144/151 patients had healed lesions without relapse at the pre-defined time point 52 weeks after start of treatment - 95.4 (90.7-98.1)%, while 140/146 - 95.9 (91.3-98.5)% in the CR8 arm were healed. The difference in proportion, - 0.5 (-5.2 - 4.2), was not significantly greater than zero (p= 0.5873) demonstrating non-inferiority. Median time to healing was 24 (IQR, 8-28) weeks in the RS8 arm, and 16 (IQR, 8-25) weeks in the CR8 arm. Adverse drug effects were more common with streptomycin-based therapy; no patients needed surgical resection; four had skin grafts. Interpretation For early, limited Buruli ulcer, oral clarithromycin-rifampicin combination treatment was non-inferior to intramuscular streptomycin-oral rifampicin treatment, and was associated with less ototoxicity.Trial registration: clinicaltrials.gov: NCT01659437.Funding: the World Health Organisation, sponsor; additional support in cash or kind was provided by MAP International, American Leprosy Missions, Raoul Follereau France, Buruli ulcer Groningen Foundation, Sanofi-Pasteur France; BuruliVac (EU FP7-241500). Declaration of Interest: All authors have no conflicts of interest to disclose.Ethical Approval: The protocol and consent forms were approved by the ethics review Committee of the Ghana Health service (GHS-ERC01/03/11) and Benin (No180 108/MS/DC/SGM/DFRS/CNPERS/SA). Ethics approval was also granted by the WHO ethics Review Committee (RPC443) and the University Medical Centre Groningen Ethics Review Board reviewed the protocol (M11.097746).