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| Name | Class |
|---|---|
| Universidad de Zaragoza | OTHER |
| Fondation Raoul Follereau | UNKNOWN |
| Université d'Abomey-Calavi | OTHER |
| Instituto de Salud Carlos III |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| RC8, Rifampicin plus Clarithromycin for 8 weeks | Active Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 (CÏ„) (pharmacokinetic parameter) for RIF, CLA and AMX for the two groups (RC8 and RCA4) at steady-state. |
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Inclusion Criteria:
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.
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Christian Johnson | Contact | 0022996221132 | rochchristianjohnson@gmail.com |
| Name | Affiliation | Role |
|---|---|---|
| Santiago Ramón-GarcÃa | Fundacion Agencia Aragonesa para la Investigacion y Desarrollo (ARAID) | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB) (Centers for Detection and Treatment of Buruli ulcer), Allada | Recruiting | Allada | Benin |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29642808 | Background | 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. | |
| 4126917 | 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. |
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| OTHER_GOV |
| Fundación Anesvad | UNKNOWN |
| Tres Cantos Open Lab Foundation | UNKNOWN |
| GlaxoSmithKline | INDUSTRY |
BLMs4BU study is a Phase II, randomized, controlled open label non-inferiority, multi-centre trial, with two treatment arms:
Randomization will be stratified by lesion category categories I, II or III, using a fixed block size within each strata.
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|
| 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. |
|
| 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 |
| Characterize the POPPK in BU patients randomised on RCA4 and derive population PK arameters, such as apparent Clearance (CL/F), together with potential covariates of interest. | This will involve investigating inter- and intra-subject variability for RIF and AMX. The Pharmacokinetic Population (POPPK) is defined as the participants in the Safety Population (SP) who receive at least one dose of randomised study medication and have at least one evaluable PK sample. Participants will be analysed according to the treatment actually received. | Between week 1 and week 2 after treatment initiation |
| Characterize the POPPK in BU patients randomised on RCA4 and derive population PK arameters, such as apparent Volume of distribution (V/F), together with potential covariates of interest. | This will involve investigating inter- and intra-subject variability for RIF and AMX. The Pharmacokinetic Population (POPPK) is defined as the participants in the Safety Population (SP) who receive at least one dose of randomised study medication and have at least one evaluable PK sample. Participants will be analysed according to the treatment actually received. | Between week 1 and week 2 after treatment initiation |
| Characterize the POPPK in BU patients randomised on RCA4 and derive population PK arameters, such as Absorption Rate (Ka), together with potential covariates of interest. | This will involve investigating inter- and intra-subject variability for RIF and AMX. The Pharmacokinetic Population (POPPK) is defined as the participants in the Safety Population (SP) who receive at least one dose of randomised study medication and have at least one evaluable PK sample. Participants will be analysed according to the treatment actually received. | Between week 1 and week 2 after treatment initiation |
| Rate of complete lesion healing without recurrence and without excision surgery, 12 months after start of treatment in the Intention-to-Treat Exposed (ITT-E) PCR+, PP Clinical Diagnose (CD), and ITT-E CD populations | Intention To Treat Exposed (ITT-E) PCR + population: The ITT-E PCR+ population includes those randomized patients with a clinical diagnosis of Very Likely BU or Likely BU, PCR+ that have, at least, taken one dose of the study drugs. This population might include major violators of the protocol. Per Protocol (PP) Clinical Diagnose (CD) population: The PP CD population includes those randomized patients with a clinical diagnosis of Very Likely BU or Likely BU and with no major violations of the protocol. This population includes both PCR+ and PCR -. Intention To Treat Exposed (ITT-E) Clinical Diagnose (CD) population: The ITT-E CD population includes those randomized patients with a clinical diagnosis of Very Likely BU or Likely BU that have, at least, taken one dose of the study drugs. This population might include both PCR+ and PCR - and major violators of the protocol. | 12 months after treatment initiation |
| Rate of complete lesion healing without recurrence and without excision surgery 12 months after start of treatment by category (I, II & III) lesions analysis in all ITT-E and PP populations | Intention-to-Treat Exposed (ITT-E): this population will consist of all randomized patients who receive at least one dose of randomized study medication. Patients will be assessed according to their randomized treatment, regardless of the treatment they receive. Per Protocol (PP): this population will consist of subjects in the ITT-E population who complete the study and are not major protocol violators. | 12 months after treatment initiation |
| Recurrence rate within 12 months of treatment initiation in all ITT-E and PP populations | Intention-to-Treat Exposed (ITT-E): this population will consist of all randomized patients who receive at least one dose of randomized study medication. Patients will be assessed according to their randomized treatment, regardless of the treatment they receive. Per Protocol (PP): this population will consist of subjects in the ITT-E population who complete the study and are not major protocol violators. | Within 12 months of treatment initiation |
| Treatment discontinuation rate in all ITT-E and PP populations | Intention-to-Treat Exposed (ITT-E): this population will consist of all randomized patients who receive at least one dose of randomized study medication. Patients will be assessed according to their randomized treatment, regardless of the treatment they receive. Per Protocol (PP): this population will consist of subjects in the ITT-E population who complete the study and are not major protocol violators. | Active comparator arm (RC8): 8 weeks; Experimental arm (RCA4): 4 weeks |
| Treatment compliance rate in all ITT-E and PP populations | Intention-to-Treat Exposed (ITT-E): this population will consist of all randomized patients who receive at least one dose of randomized study medication. Patients will be assessed according to their randomized treatment, regardless of the treatment they receive. Per Protocol (PP): this population will consist of subjects in the ITT-E population who complete the study and are not major protocol violators. | Active comparator arm (RC8): 8 weeks; Experimental arm (RCA4): 4 weeks |
| Rate of paradoxical response within 12 months of treatment initiation in all ITT-E and PP populations | Intention-to-Treat Exposed (ITT-E): this population will consist of all randomized patients who receive at least one dose of randomized study medication. Patients will be assessed according to their randomized treatment, regardless of the treatment they receive. Per Protocol (PP): this population will consist of subjects in the ITT-E population who complete the study and are not major protocol violators. | Within 12 months of treatment initiation |
| Median time to healing after treatment initiation in all ITT-E and PP populations | Intention-to-Treat Exposed (ITT-E): this population will consist of all randomized patients who receive at least one dose of randomized study medication. Patients will be assessed according to their randomized treatment, regardless of the treatment they receive. Per Protocol (PP): this population will consist of subjects in the ITT-E population who complete the study and are not major protocol violators. | Within 12 months of treatment initiation until the date of healing time |
| Proportion of patients with reduction in lesion surface area within 12 months of treatment initiation in all ITT-E and PP populations | Intention-to-Treat Exposed (ITT-E): this population will consist of all randomized patients who receive at least one dose of randomized study medication. Patients will be assessed according to their randomized treatment, regardless of the treatment they receive. Per Protocol (PP): this population will consist of subjects in the ITT-E population who complete the study and are not major protocol violators. | Within 12 months of treatment initiation |
| Interval between healing and recurrence within 12 months of treatment initiation in all ITT-E and PP populations | Intention-to-Treat Exposed (ITT-E): this population will consist of all randomized patients who receive at least one dose of randomized study medication. Patients will be assessed according to their randomized treatment, regardless of the treatment they receive. Per Protocol (PP): this population will consist of subjects in the ITT-E population who complete the study and are not major protocol violators. | Within 12 months of treatment initiation |
| Incidence of all adverse events (AEs), Serious Adverse Events (SAE), Serious unexpected suspected adverse drug reactions (SUSAR) within 12 months of treatment initiation among treatment arms in all ITT-E and PP populations | Intention-to-Treat Exposed (ITT-E): this population will consist of all randomized patients who receive at least one dose of randomized study medication. Patients will be assessed according to their randomized treatment, regardless of the treatment they receive. Per Protocol (PP): this population will consist of subjects in the ITT-E population who complete the study and are not major protocol violators. | Within 12 months of treatment initiation |
| Rate of median bacterial clearance among treatment arms in the bacterial clearance sub-study population | Within 8 weeks or 14 weeks after treatment initiation according to the healing time |
| Rate of patients with Buruli ulcer Functional Limitation Score (BUFLS) improvement within 12 months of treatment initiation among treatment arms in all ITT-E and PP populations | Intention-to-Treat Exposed (ITT-E): this population will consist of all randomized patients who receive at least one dose of randomized study medication. Patients will be assessed according to their randomized treatment, regardless of the treatment they receive. Per Protocol (PP): this population will consist of subjects in the ITT-E population who complete the study and are not major protocol violators. | Within 12 months of treatment initiation |
| Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB) (Centers for Detection and Treatment of Buruli ulcer), Lalo | Recruiting | Lalo | Benin |
|
| Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB) (Centers for Detection and Treatment of Buruli ulcer), Pobè | Recruiting | Pobè | Benin |
|
| 12044304 | 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. |
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| Background | World Health Organization. Treatment of Mycobacterium ulcerans infection. 2012 |
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| 26157437 | 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. |
| 30556580 | 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. |
| 27678056 | 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. |
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| 28671942 | 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. |
| 20625556 | 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. |
| 24731247 | 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. |
| 31449522 | 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. |
| 32091710 | 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/ |
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| 32171422 | 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. |
| 29605498 | 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. |
| 8582154 | 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. |
| 42104494 | Derived | Calvet-Seral J, Saez-Lopez E, Lopez-Exposito PR, Ferrer-Bazaga S, Vaquero JJ, Ramon-Garcia S, Mendoza-Losana A. The ribosomal RNA synthesis ratio biomarker in Mycobacterium ulcerans for drug activity evaluation. Infect Dis Poverty. 2026 May 8;15(1):51. doi: 10.1186/s40249-026-01449-2. |
| 38573915 | Derived | 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. |
| 35804454 | 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. |
| ID | Term |
|---|---|
| D054312 | Buruli Ulcer |
| D058069 | Neglected Diseases |
| ID | Term |
|---|---|
| D009165 | Mycobacterium Infections, Nontuberculous |
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| D012883 | Skin Ulcer |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
Not provided
Not provided
| ID | Term |
|---|---|
| D017291 | Clarithromycin |
| D013812 | Therapeutics |
| D019818 | Clavulanic Acid |
| D000074584 | WW Domain-Containing Oxidoreductase |
| ID | Term |
|---|---|
| D004917 | Erythromycin |
| D018942 | Macrolides |
| D061065 | Polyketides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
| D002969 | Clavulanic Acids |
| D047090 | beta-Lactams |
| D007769 | Lactams |
| D000577 | Amides |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D000074583 | Short Chain Dehydrogenase-Reductases |
| D064430 | NAD (+) and NADP (+) Dependent Alcohol Oxidoreductases |
| D000429 | Alcohol Oxidoreductases |
| D010088 | Oxidoreductases |
| D004798 | Enzymes |
| D045762 | Enzymes and Coenzymes |
| D025521 | Tumor Suppressor Proteins |
| D009363 | Neoplasm Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
Not provided
Not provided