Format

Send to

Choose Destination
Lancet. 2020 Mar 12. pii: S0140-6736(20)30047-7. doi: 10.1016/S0140-6736(20)30047-7. [Epub ahead of print]

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

Author information

1
Kwame Nkrumah University of Science and Technology, Kumasi Centre for Collaborative Research in Tropical Medicine, Komfo Anokye Teaching Hospital, Kumasi, Ghana.
2
Centre d'immunologie et des maladies infectieuses, Inserm, Sorbonne Université, Bactériologie site Pitié, AP-HP Sorbonne Université, Centre National de Référence des Mycobactéries, Paris, France.
3
Agogo Presbyterian Hospital, Agogo, Ghana.
4
Nkawie-Toaso Government Hospital, Ghana.
5
Dunkwa Government Hospital, Dunkwa-on-Offin, Ghana.
6
Centre de diagnostic et de traitement de la lèpre et de l'Ulcère de Buruli Madeleine et Raoul Follereau, Ouémé-Plateau, Pobè, Bénin.
7
Drugs for Neglected Diseases initiative, Africa Regional Office, Nairobi, Kenya.
8
National Buruli ulcer Control Programme, Ghana Health Service, Accra, Ghana.
9
Programme National de Lutte contre la lèpre et l'Ulcère de Buruli, Cotonou, Benin.
10
Centre de recherche en cancérologie et immunologie Nantes-Angers, French National Institute of Health and Medical Research, Université d'Angers, Angers, France.
11
Institute of Infection and Immunity, St George's University of London, London, UK.
12
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
13
Department of Dermatology & Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA; Hospital Bernard Meys Project Medishare, Port-au-Prince, Haiti.
14
Institute for Advanced Wound Care, Montgomery, AL, USA.
15
American Leprosy Missions, Greenville, SC, USA.
16
Reconstructive and Plastic Surgery Unit, Korle-BU Teaching Hospital, Accra, Ghana.
17
WHO, Country Office for Benin, Cotonou, Benin.
18
WHO, Regional Office for Africa, Brazzaville, Republic of the Congo.
19
WHO, Country Office for Ghana, Accra, Ghana.
20
Department of Medicine/Infectious Diseases, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands.
21
Department of Neglected Tropical Diseases, WHO, Geneva, Switzerland.
22
Department of Medicine/Infectious Diseases, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands. Electronic address: t.s.van.der.werf@umcg.nl.

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.

PMID:
32171422
DOI:
10.1016/S0140-6736(20)30047-7
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center