Beta-Lactam Containing Regimen for the Shortening of Buruli Ulcer Disease Therapy

NCT05169554 | Recruiting Phase 2 DMC

• 1 other identifier: TC281
• Study Type: interventional
• Target: 140
• Locations: 1 country
• Sites: 3

Brief Summary

Buruli ulcer (BU) is a skin Neglected Tropical Disease (NTD) that is caused by Mycobacterium ulcerans. It affects skin, soft tissues and bones causing long-term morbidity, stigma and disability. The greatest burden falls on children in sub-Saharan Africa. Treating BU requires 8-weeks with daily rifampicin and clarithromycin, wound care, and sometimes tissue grafting and surgery. Healing can take up to one year. Compliance is challenging due to socioeconomic determinants and may pose an unbearable financial burden to the household. Recent studies led by members of this Consortium demonstrated that beta-lactams combined with rifampicin and clarithromycin are synergistic against M. ulcerans in vitro. Amoxicillin/clavulanate is oral, suitable for treatment in adults and children, and readily available with an established clinical pedigree. Its inclusion in a triple oral BU therapy has the potential of improving healing and shortening BU therapy. The investigators propose a single blinded, randomized, controlled open label non-inferiority phase II, multi-centre trial in Benin with participants stratified according to BU category lesions and randomized in two oral regimens: (i) Standard \[RC8\]: rifampicin plus clarithromycin (RC) therapy for 8 weeks; and (ii) Investigational \[RCA4\]: standard (RC) plus amoxicillin/clavulanate (A) for 4 weeks. At least, a total of 140 patients will be recruited (70 per treatment arm), of which at least 132 will be PCR-confirmed. The primary efficacy outcome will be lesion healing without recurrence and without excision surgery 12 months after start of treatment (i.e. cure). A clinical expert panel assessing the need of excision surgery in both treatment arms will be blinded for treatment allocation in order to make objectives comparisons. Decision for excision surgery will be delayed to 14 weeks after initiation of antibiotic treatment. Secondary clinical efficacy outcomes include recurrence, treatment discontinuation and compliance rates, and the incidence of adverse effects, among others. In addition, two sub-studies will be performed: a pharmacokinetic (PK) analysis and a bacterial clearance study. If successful, this study will create a new paradigm for BU treatment, which could inform changes in WHO policy and practice. This trial may also provide information on treatment shortening strategies for other mycobacterial infections, such as tuberculosis or leprosy.

Conditions

Buruli Ulcer

Keywords

Buruli ulcer; Neglected tropical disease; Treatment shortening; Drug combination; Amoxicillin/clavulanate; Clinical trial; Pharmacokinetic analysis; Bacterial clearance study

Outcome Measures

Primary Outcomes (1)

• Cure rate, i.e. proportion of patients with complete lesion healing without recurrence and without excision surgery 12 months after treatment initiation, in the Per Protocol (PP) PCR+ population

  The PP PCR+ population includes those randomized patients with a clinical diagnosis of Very Likely BU or Likely BU, PCR+ and with no major violations of the protocol.

  12 months after treatment initiation

Secondary Outcomes (20)

• Derive and compare the Area Under the Curve (AUC) (pharmacokinetic parameter) for RIF, CLA and AMX for the two groups (RC8 and RCA4) at steady-state.

  Between week 1 and week 2 after treatment initiation

• Derive and compare the trough concentration (Cτ) (pharmacokinetic parameter) for RIF, CLA and AMX for the two groups (RC8 and RCA4) at steady-state.

  Between week 1 and week 2 after treatment initiation

• Derive and compare the maximum observed drug concentration (Cmax) (pharmacokinetic parameter) for RIF, CLA and AMX for the two groups (RC8 and RCA4) at steady-state.

  Between week 1 and week 2 after treatment initiation

• Derive and compare the time to maximum observed drug concentration (tmax) (pharmacokinetic parameter) for RIF, CLA and AMX for the two groups (RC8 and RCA4) at steady-state.

  Between week 1 and week 2 after treatment initiation

• Derive and compare the elimination half-life (t1/2) (pharmacokinetic parameter) for RIF, CLA and AMX for the two groups (RC8 and RCA4) at steady-state.

  Between week 1 and week 2 after treatment initiation

Study Arms (2)

RC8, Rifampicin plus Clarithromycin for 8 weeks

ACTIVE COMPARATOR

Rifampicin plus Clarithromycin (RC) therapy for 8 weeks

Drug: Standard [RC8]: rifampicin plus clarithromycin (RC) therapy for 8 weeks.

RCA4, Rifampicin plus Clarithromycin plus Amoxicillin/clavulanate for 4 weeks.

EXPERIMENTAL

Rifampicin plus Clarithromycin (RC) plus Amoxicillin/clavulanate (A) for 4 weeks.

Drug: Investigational [RCA4]: standard (RC) plus amoxicillin/clavulanate (A) for 4 weeks.

Interventions

Standard [RC8]: rifampicin plus clarithromycin (RC) therapy for 8 weeks. DRUG

Treatment will be rifampicin (600 mg, daily) and clarithromycin (500 mg, twice daily) for 8 weeks. On the posology, dosage for rifampicin and clarithromycin will be standardized according to patient body weight following WHO guidelines. In general, for a 60 kg adult dosage will be RIF, 10 mg/kg once daily and CLA, 7.5 mg/kg twice daily.

RC8, Rifampicin plus Clarithromycin for 8 weeks

Investigational [RCA4]: standard (RC) plus amoxicillin/clavulanate (A) for 4 weeks. DRUG

On the posology, dosage for rifampicin and clarithromycin will be standardized according to patient body weight following WHO guidelines. In general, for a 60 kg adult dosage will be RIF, 10 mg/kg once daily and CLA, 7.5 mg/kg twice daily. Dosages for amoxicillin/clavulanate are calculated according to manufacturer indications: Dose of amoxicillin/clavulanate 1000/125 mg twice daily, which makes a total of 2000/250 mg/day, for patients over 40 kg, and 22.5/5.6 mg/kg twice daily, which makes a total of 45/11.25 mg/kg/day, for those equal and below 40 kg. For children, posology will be adapted to the age of the patient according to drug manufacturer indications. Frequency of AMX/CLV administration will match that of CLA, twice daily.

RCA4, Rifampicin plus Clarithromycin plus Amoxicillin/clavulanate for 4 weeks.

Eligibility Criteria

• Age: 5 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• All patients (both genders) with a new very likely or likely (WHO scoring criteria) clinical diagnosis of BU (all categories: I, II, III) and normal electrocardiogram (ECG) at baseline giving informed consent will be included in the study, as agreed by study site treatment team led by the lead clinicians.

You may not qualify if:

• Children \< 5 years and adults \>70 years.
• Children in foster care.
• Patients weighing less than 11 kilograms.
• Pregnancy positive (urine test: beta-HCG positive).
• Previous treatment of Buruli ulcer, tuberculosis or leprosy with at least one of the study drugs.
• Patients with diagnose leprosy or tuberculosis disease.
• Hypersensitivity to at least one of the study drugs or to any of the excipients.
• History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam).
• History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid or rifampicin.
• Patients with history of treatment with macrolide or quinolone antibiotics, anti-tuberculosis medication, or immuno-modulatory drugs including corticosteroids within one month.
• Patients currently receiving treatment with any drugs likely to interact with the study medications, i.e. anticoagulants, cyclosporine, phenytoin or phenobarbitone. Users of oral contraceptives should be notified that such contraceptive is less reliable if taken with rifampicin; additional (mechanical) contraceptive methods will be discussed with the study participant (Appendix 5).
• Patients with HIV co-infection.
• Patients with QTc prolongation \>450 ms on ECG or on other medication known to prolong the QTc interval. In this case, if suspected of BU disease, patients will be offered 8-weeks rifampicin plus streptomycin therapy.
• Patients unable to take oral medication or having gastrointestinal disease likely to interfere with drug absorption.
• Patients with history or having current clinical signs of ascites, jaundice, myasthenia gravis, renal dysfunction (known or suspected), diabetes mellitus, and severe immune compromise, or evidence of tuberculosis, or leprosy; terminal illness (e.g., metastasized cancer), haematological malignancy, chronic liver disease, abnormal liver function test and coronary artery disease or any other condition that would preclude enrolment into the study in the study physician's opinion.

Sponsors & Collaborators

• Fundacion Agencia Aragonesa para la Investigacion y Desarrollo (ARAID): lead
• Universidad de Zaragoza: collaborator
• Fondation Raoul Follereau: collaborator
• Université d'Abomey-Calavi: collaborator
• Instituto de Salud Carlos III: collaborator
• Fundación Anesvad: collaborator
• Tres Cantos Open Lab Foundation: collaborator
• GlaxoSmithKline: collaborator

Study Sites (3)

Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB) (Centers for Detection and Treatment of Buruli ulcer), Allada

Allada, Benin

RECRUITING

Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB) (Centers for Detection and Treatment of Buruli ulcer), Lalo

Lalo, Benin

RECRUITING

Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB) (Centers for Detection and Treatment of Buruli ulcer), Pobè

Pobè, Benin

RECRUITING

Related Publications (26)

• O'Brien DP, Athan E, Blasdell K, De Barro P. Tackling the worsening epidemic of Buruli ulcer in Australia in an information void: time for an urgent scientific response. Med J Aust. 2018 Apr 16;208(7):287-289. doi: 10.5694/mja17.00879. No abstract available.

  PMID: 29642808 BACKGROUND

• Revill WD, Morrow RH, Pike MC, Ateng J. A controlled trial of the treatment of Mycobacterium ulcerans infection with clofazimine. Lancet. 1973 Oct 20;2(7834):873-7. doi: 10.1016/s0140-6736(73)92005-9. No abstract available.

  PMID: 4126917 BACKGROUND

• Espey DK, Djomand G, Diomande I, Dosso M, Saki MZ, Kanga JM, Spiegel RA, Marston BJ, Gorelkin L, Meyers WM, Portaels F, Deming MS, Horsburgh CR Jr. A pilot study of treatment of Buruli ulcer with rifampin and dapsone. Int J Infect Dis. 2002 Mar;6(1):60-5. doi: 10.1016/s1201-9712(02)90138-4.

  PMID: 12044304 BACKGROUND

• Guarner J. Buruli Ulcer: Review of a Neglected Skin Mycobacterial Disease. J Clin Microbiol. 2018 Mar 26;56(4):e01507-17. doi: 10.1128/JCM.01507-17. Print 2018 Apr.

  PMID: 29343539 BACKGROUND

• Thangaraj HS, Adjei O, Allen BW, Portaels F, Evans MR, Banerjee DK, Wansbrough-Jones MH. In vitro activity of ciprofloxacin, sparfloxacin, ofloxacin, amikacin and rifampicin against Ghanaian isolates of Mycobacterium ulcerans. J Antimicrob Chemother. 2000 Feb;45(2):231-3. doi: 10.1093/jac/45.2.231.

  PMID: 10660507 BACKGROUND

• World Health Organization. Treatment of Mycobacterium ulcerans infection. 2012

  BACKGROUND

• Boeree MJ, Diacon AH, Dawson R, Narunsky K, du Bois J, Venter A, Phillips PP, Gillespie SH, McHugh TD, Hoelscher M, Heinrich N, Rehal S, van Soolingen D, van Ingen J, Magis-Escurra C, Burger D, Plemper van Balen G, Aarnoutse RE; PanACEA Consortium. A dose-ranging trial to optimize the dose of rifampin in the treatment of tuberculosis. Am J Respir Crit Care Med. 2015 May 1;191(9):1058-65. doi: 10.1164/rccm.201407-1264OC.

  PMID: 25654354 BACKGROUND

• Hu Y, Liu A, Ortega-Muro F, Alameda-Martin L, Mitchison D, Coates A. High-dose rifampicin kills persisters, shortens treatment duration, and reduces relapse rate in vitro and in vivo. Front Microbiol. 2015 Jun 23;6:641. doi: 10.3389/fmicb.2015.00641. eCollection 2015.

  PMID: 26157437 BACKGROUND

• Omansen TF, Stienstra Y, van der Werf TS. Treatment for Buruli ulcer: the long and winding road to antimicrobials-first. Cochrane Database Syst Rev. 2018 Dec 17;12(12):ED000128. doi: 10.1002/14651858.ED000128. No abstract available.

  PMID: 30556580 BACKGROUND

• Ramon-Garcia S, Gonzalez Del Rio R, Villarejo AS, Sweet GD, Cunningham F, Barros D, Ballell L, Mendoza-Losana A, Ferrer-Bazaga S, Thompson CJ. Repurposing clinically approved cephalosporins for tuberculosis therapy. Sci Rep. 2016 Sep 28;6:34293. doi: 10.1038/srep34293.

  PMID: 27678056 BACKGROUND

• Arenaz-Callao MP, Gonzalez Del Rio R, Lucia Quintana A, Thompson CJ, Mendoza-Losana A, Ramon-Garcia S. Triple oral beta-lactam containing therapy for Buruli ulcer treatment shortening. PLoS Negl Trop Dis. 2019 Jan 28;13(1):e0007126. doi: 10.1371/journal.pntd.0007126. eCollection 2019 Jan.

  PMID: 30689630 BACKGROUND

• Rolinson GN. Forty years of beta-lactam research. J Antimicrob Chemother. 1998 Jun;41(6):589-603. doi: 10.1093/jac/41.6.589.

  PMID: 9687097 BACKGROUND

• Diacon AH, van der Merwe L, Barnard M, von Groote-Bidlingmaier F, Lange C, Garcia-Basteiro AL, Sevene E, Ballell L, Barros-Aguirre D. beta-Lactams against Tuberculosis--New Trick for an Old Dog? N Engl J Med. 2016 Jul 28;375(4):393-4. doi: 10.1056/NEJMc1513236. Epub 2016 Jul 13. No abstract available.

  PMID: 27433841 BACKGROUND

• Ma Z, Lienhardt C, McIlleron H, Nunn AJ, Wang X. Global tuberculosis drug development pipeline: the need and the reality. Lancet. 2010 Jun 12;375(9731):2100-9. doi: 10.1016/S0140-6736(10)60359-9. Epub 2010 May 18.

  PMID: 20488518 BACKGROUND

• Ramon-Garcia S, Ng C, Anderson H, Chao JD, Zheng X, Pfeifer T, Av-Gay Y, Roberge M, Thompson CJ. Synergistic drug combinations for tuberculosis therapy identified by a novel high-throughput screen. Antimicrob Agents Chemother. 2011 Aug;55(8):3861-9. doi: 10.1128/AAC.00474-11. Epub 2011 May 16.

  PMID: 21576426 BACKGROUND

• Sarpong-Duah M, Frimpong M, Beissner M, Saar M, Laing K, Sarpong F, Loglo AD, Abass KM, Frempong M, Sarfo FS, Bretzel G, Wansbrough-Jones M, Phillips RO. Clearance of viable Mycobacterium ulcerans from Buruli ulcer lesions during antibiotic treatment as determined by combined 16S rRNA reverse transcriptase /IS 2404 qPCR assay. PLoS Negl Trop Dis. 2017 Jul 3;11(7):e0005695. doi: 10.1371/journal.pntd.0005695. eCollection 2017 Jul.

  PMID: 28671942 BACKGROUND

• Kibadi K, Boelaert M, Fraga AG, Kayinua M, Longatto-Filho A, Minuku JB, Mputu-Yamba JB, Muyembe-Tamfum JJ, Pedrosa J, Roux JJ, Meyers WM, Portaels F. Response to treatment in a prospective cohort of patients with large ulcerated lesions suspected to be Buruli Ulcer (Mycobacterium ulcerans disease). PLoS Negl Trop Dis. 2010 Jul 6;4(7):e736. doi: 10.1371/journal.pntd.0000736.

  PMID: 20625556 BACKGROUND

• Sarfo FS, Phillips RO, Zhang J, Abass MK, Abotsi J, Amoako YA, Adu-Sarkodie Y, Robinson C, Wansbrough-Jones MH. Kinetics of mycolactone in human subcutaneous tissue during antibiotic therapy for Mycobacterium ulcerans disease. BMC Infect Dis. 2014 Apr 15;14:202. doi: 10.1186/1471-2334-14-202.

  PMID: 24731247 BACKGROUND

• Frimpong M, Agbavor B, Duah MS, Loglo A, Sarpong FN, Boakye-Appiah J, Abass KM, Dongyele M, Amofa G, Tuah W, Frempong M, Amoako YA, Wansbrough-Jones M, Phillips RO. Paradoxical reactions in Buruli ulcer after initiation of antibiotic therapy: Relationship to bacterial load. PLoS Negl Trop Dis. 2019 Aug 26;13(8):e0007689. doi: 10.1371/journal.pntd.0007689. eCollection 2019 Aug.

  PMID: 31449522 BACKGROUND

• Roltgen K, Pluschke G. Buruli Ulcer: History and Disease Burden. 2019 Apr 30. In: Pluschke G, Roltgen K, editors. Buruli Ulcer: Mycobacterium Ulcerans Disease [Internet]. Cham (CH): Springer; 2019. Available from http://www.ncbi.nlm.nih.gov/books/NBK553836/

  PMID: 32091710 BACKGROUND

• Omansen TF, van der Werf TS, Phillips RO. Antimicrobial Treatment of Mycobacterium ulcerans Infection. 2019 Apr 30. In: Pluschke G, Roltgen K, editors. Buruli Ulcer: Mycobacterium Ulcerans Disease [Internet]. Cham (CH): Springer; 2019. Available from http://www.ncbi.nlm.nih.gov/books/NBK553822/

  PMID: 32091697 BACKGROUND

• Phillips RO, Robert J, Abass KM, Thompson W, Sarfo FS, Wilson T, Sarpong G, Gateau T, Chauty A, Omollo R, Ochieng Otieno M, Egondi TW, Ampadu EO, Agossadou D, Marion E, Ganlonon L, Wansbrough-Jones M, Grosset J, Macdonald JM, Treadwell T, Saunderson P, Paintsil A, Lehman L, Frimpong M, Sarpong NF, Saizonou R, Tiendrebeogo A, Ohene SA, Stienstra Y, Asiedu KB, van der Werf TS; study team. Rifampicin and clarithromycin (extended release) versus rifampicin and streptomycin for limited Buruli ulcer lesions: a randomised, open-label, non-inferiority phase 3 trial. Lancet. 2020 Apr 18;395(10232):1259-1267. doi: 10.1016/S0140-6736(20)30047-7. Epub 2020 Mar 12.

  PMID: 32171422 BACKGROUND

• Wadagni AC, Barogui YT, Johnson RC, Sopoh GE, Affolabi D, van der Werf TS, de Zeeuw J, Kleinnijenhuis J, Stienstra Y. Delayed versus standard assessment for excision surgery in patients with Buruli ulcer in Benin: a randomised controlled trial. Lancet Infect Dis. 2018 Jun;18(6):650-656. doi: 10.1016/S1473-3099(18)30160-9. Epub 2018 Apr 5.

  PMID: 29605498 BACKGROUND

• Sato T. A further look at the Cochran-Mantel-Haenszel risk difference. Control Clin Trials. 1995 Oct;16(5):359-61. doi: 10.1016/0197-2456(95)00004-6. No abstract available.

  PMID: 8582154 BACKGROUND

• Saez-Lopez E, Millan-Placer AC, Lucia A, Ramon-Garcia S. Amoxicillin/clavulanate in combination with rifampicin/clarithromycin is bactericidal against Mycobacterium ulcerans. PLoS Negl Trop Dis. 2024 Apr 4;18(4):e0011867. doi: 10.1371/journal.pntd.0011867. eCollection 2024 Apr.

  PMID: 38573915 DERIVED

• Johnson RC, Saez-Lopez E, Anagonou ES, Kpoton GG, Ayelo AG, Gnimavo RS, Mignanwande FZ, Houezo JG, Sopoh GE, Addo J, Orford L, Vlasakakis G, Biswas N, Calderon F, Della Pasqua O, Gine-March A, Herrador Z, Mendoza-Losana A, Diez G, Cruz I, Ramon-Garcia S. 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. Trials. 2022 Jul 8;23(1):559. doi: 10.1186/s13063-022-06473-9.

  PMID: 35804454 DERIVED

MeSH Terms

Conditions

Buruli Ulcer; Neglected Diseases

Interventions

Clarithromycin; Therapeutics; Clavulanic Acid; WW Domain-Containing Oxidoreductase

Condition Hierarchy (Ancestors)

Mycobacterium Infections, Nontuberculous; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Skin Ulcer; Skin Diseases; Skin and Connective Tissue Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals; Clavulanic Acids; beta-Lactams; Lactams; Amides; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Short Chain Dehydrogenase-Reductases; NAD (+) and NADP (+) Dependent Alcohol Oxidoreductases; Alcohol Oxidoreductases; Oxidoreductases; Enzymes; Enzymes and Coenzymes; Tumor Suppressor Proteins; Neoplasm Proteins; Proteins; Amino Acids, Peptides, and Proteins

Study Officials

• Santiago Ramón-García

  Fundacion Agencia Aragonesa para la Investigacion y Desarrollo (ARAID)

  STUDY DIRECTOR

Central Study Contacts

Christian Johnson

CONTACT

0022996221132; rochchristianjohnson@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: BLMs4BU study is a Phase II, randomized, controlled open label non-inferiority, multi-centre trial, with two treatment arms: * Standard \[RC8\]: rifampicin plus clarithromycin (RC) therapy for 8 weeks; and * Investigational \[RCA4\]: standard (RC) plus amoxicillin/clavulanate (A) for 4 weeks. Randomization will be stratified by lesion category categories I, II or III, using a fixed block size within each strata.

Study Record Dates

• First Submitted: November 22, 2021
• First Posted: December 27, 2021
• Study Start: December 1, 2021
• Primary Completion (Estimated): May 31, 2026
• Study Completion (Estimated): May 31, 2026
• Last Updated: May 16, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

BE (3)