Alan Knell, Thomas Berko, Linda Lehman, Tuah Wilson, Sarah Eyangoh, Kingsley Asiedu, Ernest Opoku, Kristien Velding, Edwin Ampadu, Jérôme Robert, Estelle Marion, Bright Osei-Wusu, Annick Chauty, Edward Sarpong, William Faber, Anastasia Nsiah, Ambroise Adeye, Yaw Ampem Amoako, Marie Françoise Ardent, William Thompson, George Amofa, Richard Phillips, Line Ganlonon, John M Macdonald, Elliot Koranteng Tannor, Till F. Omansen, Raymond Omollo, Terry Treadwell, Justice Abotsi, Albert Paintsil, Nanaa Francisca Sarpong, Samuel Osei Mireku, Maxime Kiki, Raoul Saizonou, David Ofori-Adjei, Bernadette Agbavor, Godfred Sarpong, Espoir Sodjinou, Michael Ochieng Otieno, Fred Stephen Sarfo, Paul Saunderson, Aloysius Dzibordzi Loglo, Martial Kindjinou, Justice K. Boakye-Appiah, Beatrice Konadu, Arnaud Yamadjako, Didier Agossadou, Mark Forson, Tjip S. van der Werf, Sally-Ann Ohene, Elizabeth Ofori, Mathias Ndogyele, Ymkje Stienstra, Thaddaeus Egondi, Richard Asamoah-Frimpong, Joseph Ken Adu Poku, Mabel Sarpong-Duah, Joyce Mensah-Bonsu, Felicity Aboagye, Thierry Gateau, Michael Frimpong, Joseph Ofori Nyarko, Mark Wansbrough-Jones, Kabiru Mohamed Abass, Clémence Guegnard, Alexandre Tiendrebeogo, Akpolan, Jacques H. Grosset, Sandor-Adrian Klis, Naomi Adanmado Gersande, Bernardo, Elizabeth, Identification and development of vaccine candidates for Buruli Ulcer Disease - BURULIVAC - - EC:FP7:HEALTH2010-03-01 - 2013-05-31 - 241500 - VALID, Kwame Nkrumah University of Science and Technology [GHANA] (KNUST), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Agogo Presbyterian Hospital [GHANA], NkawieToaso Government Hospital [GHANA], Centre de diagnostic et de traitement de la lèpre et de l’Ulcère de Buruli Madeleine et Raoul Follereau [Pobè, Bénin], Drugs for Neglected Diseases initiative [Nairobi, Kenya] (ARO), Africa Regional Office [Nairobi, Kenya], National Buruli ulcer Control Programme [Accra, Ghana] (GHS), Ghana Health Service [Accra, Ghana], Programme National de Lutte contre la lèpre et l’Ulcère de Buruli [Cotonou, Benin], ATOMycA (CRCINA-ÉQUIPE 6), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), St George's, University of London, Johns Hopkins University (JHU), University of Miami Leonard M. Miller School of Medicine (UMMSM), Institute for Advanced Wound Care [Montgomery, AL, USA], American Leprosy Missions [Greenville, SC, USA], Korle-BU Teaching Hospital [Accra, Ghana], WHO, Country Office for Benin [Cotonou, Benin], WHO, Regional Office for Africa [Brazzaville, Republic of the Congo], WHO, Country Office for Ghana [Accra, Ghana], University Medical Center Groningen [Groningen] (UMCG), Department of Neglected Tropical Diseases, WHO [Geneva, Switzerland], WHO sponsored the study with additional support in cash or kindprovided by MAP International, American Leprosy Missions, Fondation Raoul Follereau France, Buruli ulcer Groningen Foundation, SanofiPasteur France, and BuruliVac (EU FP7-241500)., European Project: 241500,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,BURULIVAC(2010), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Microbes in Health and Disease (MHD), and Kwame Nkrumah University of Science and Technology (KNUST)
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.