Comparison of 8 weeks standard treatment (rifampicin plus clarithromycin) vs. 4 weeks standard plus amoxicillin/clavulanate treatment [RC8 vs. RCA4] to shorten Buruli ulcer disease therapy (the BLMs4BU trial): study protocol for a randomized controlled multi-centre trial in Benin

Roch Christian Johnson, Emma Sáez-López, Esaï Sèdjro Anagonou, Godwin Gérard Kpoton, Adjimon Gilbert Ayelo, Ronald Sètondji Gnimavo, Franck Zinsou Mignanwande, Jean-Gabin Houezo, Ghislain Emmanuel Sopoh, Juliet Addo, Lindsay Orford, Georgios Vlasakakis, Nandita Biswas, Felix Calderon, Oscar Della Pasqua, Anna Gine-March, Zaida Herrador, Alfonso Mendoza-Losana, Gabriel Díez, Israel Cruz, Santiago Ramón-García, Roch Christian Johnson, Emma Sáez-López, Esaï Sèdjro Anagonou, Godwin Gérard Kpoton, Adjimon Gilbert Ayelo, Ronald Sètondji Gnimavo, Franck Zinsou Mignanwande, Jean-Gabin Houezo, Ghislain Emmanuel Sopoh, Juliet Addo, Lindsay Orford, Georgios Vlasakakis, Nandita Biswas, Felix Calderon, Oscar Della Pasqua, Anna Gine-March, Zaida Herrador, Alfonso Mendoza-Losana, Gabriel Díez, Israel Cruz, Santiago Ramón-García

Abstract

Background: Buruli ulcer (BU) is a neglected tropical disease caused by Mycobacterium ulcerans that affects skin, soft tissues, and bones, causing long-term morbidity, stigma, and disability. The recommended treatment for BU requires 8 weeks of daily rifampicin and clarithromycin together with wound care, physiotherapy, and sometimes tissue grafting and surgery. Recovery can take up to 1 year, and it may pose an unbearable financial burden to the household. Recent in vitro studies demonstrated that beta-lactams combined with rifampicin and clarithromycin are synergistic against M. ulcerans. Consequently, inclusion of amoxicillin/clavulanate in a triple oral therapy may potentially improve and shorten the healing process. The BLMs4BU trial aims to assess whether co-administration of amoxicillin/clavulanate with rifampicin and clarithromycin could reduce BU treatment from 8 to 4 weeks.

Methods: We propose a randomized, controlled, open-label, parallel-group, non-inferiority phase II, multi-centre trial in Benin with participants stratified according to BU category lesions and randomized to two oral regimens: (i) Standard: rifampicin plus clarithromycin therapy for 8 weeks; and (ii) Investigational: standard plus amoxicillin/clavulanate for 4 weeks. The primary efficacy outcome will be lesion healing without recurrence and without excision surgery 12 months after start of treatment (i.e. cure rate). Seventy clinically diagnosed BU patients will be recruited per arm. Patients will be followed up over 12 months and managed according to standard clinical care procedures. Decision for excision surgery will be delayed to 14 weeks after start of treatment. Two sub-studies will also be performed: a pharmacokinetic and a microbiology study.

Discussion: If successful, this study will create a new paradigm for BU treatment, which could inform World Health Organization policy and practice. A shortened, highly effective, all-oral regimen will improve care of BU patients and will lead to a decrease in hospitalization-related expenses and indirect and social costs and improve treatment adherence. This trial may also provide information on treatment shortening strategies for other mycobacterial infections (tuberculosis, leprosy, or non-tuberculous mycobacteria infections).

Trial registration: ClinicalTrials.gov NCT05169554 . Registered on 27 December 2021.

Keywords: Amoxicillin; Bacterial clearance; Buruli ulcer; Clavulanate; Drug combination; Non-inferiority; Pharmacokinetics; Skin neglected tropical disease; Treatment shortening.

Conflict of interest statement

JA, LO, GV, NB, and FC hold stocks and are employees by the GSK group of companies. The authors declare that they have no competing interests. GSK is independent of the Tres Cantos Open Lab Foundation which is overseen by a governing board (TCOLF https://www.openlabfoundation.org). The opinions expressed in this article are those of the authors and do not necessarily reflect the views of their employers.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Flow chart of sampling, recruitment and timelines of the clinical trial
Fig. 2
Fig. 2
Schedule of screening, randomization, interventions and assessment of the patients in the BLMs4BU study. AEs, adverse events; BUFLS, Buruli Ulcer Functional Limitation Score; FNA, fine-needle aspiration; M, month; HIV, human immunodeficiency virus; PCR, polymerase chain reaction; RC8, 8 weeks of rifampicin-clarithromycin; RCA4, 4 weeks of rifampicin-clarithromycin plus amoxicillin/clavulanate; SAEs, serious adverse events; W, week. *PK analysis (blood samples). It will be performed between days 7 and 14 after starting the treatment, prior to the second daily dose of CLA and AMX/CLV. Sampling times will include a pre-dose at time 0 (within 10 min pre-dose) and at times 0.5, 1, 1.5, 2, 2.5, 3, 5, 7.5, and 10 h post-dose
Fig. 3
Fig. 3
Location of the Lalo, Allada, and Pobè clinical sites in Benin, where the study will be conducted. Figure made with mapchart.net [21]
Fig. 4
Fig. 4
WHO clinical diagnosis scoring criteria

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