Buruli UlcerPhase 2BLMs4BUNCT05169554
Beta-Lactam Containing Regimen for the Shortening of Buruli Ulcer Disease Therapy
A Phase 2 study testing Standard [RC8]: rifampicin plus clarithromycin (RC) therapy for 8 weeks. and Investigational [RCA4]: standard (RC) plus amoxicillin/clavulanate (A) for 4 weeks. in people with Buruli Ulcer, run by Fundacion Agencia Aragonesa para la Investigacion y Desarrollo (ARAID) at 3 sites in Benin.
Trial 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. Read more about this study
- Who is it for?
- Ages 5 to 70 years
- Conditions the study is for
- Buruli Ulcer
- What is being tested?
- Standard [RC8]: rifampicin plus clarithromycin (RC) therapy for 8 weeks. and Investigational [RCA4]: standard (RC) plus amoxicillin/clavulanate (A) for 4 weeks.
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 140 participants
- Where
- 3 sitesBenin
- Study dates
- 1 Dec 2021to 31 May 2026
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 5 to 70 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 20Show fewer
- 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.
- Evidence of a clinically significant (as judged by the Investigator) condition or abnormality (other than the indication being studied) that might compromise safety or the interpretation of trial efficacy or safety endpoints
- Patients with known or suspected bowel strictures who cannot tolerate clarithromycin.
- Patients with a mental health condition that is likely to interfere with compliance with the study protocol in the opinion of the study physician.
- Patients (or parent/legal representative) who are not willing to give informed consent or withdrawal of consent.
- Specific exclusion criteria for the PK sub-study are patients less than 15 years old or less than 40 kg or with renal impairment with a creatinine level higher than the normal one in Benin (7-14 mg/L).
Trial locations and contacts
3 sites in 1 country.
Benin3 sites, 3 recruiting
- Recruiting
Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB) (Centers for Detection and Treatment of Buruli ulcer), Allada
Allada
Gilbert Ayelo, gilvinos@yahoo.fr
- Recruiting
Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB) (Centers for Detection and Treatment of Buruli ulcer), Lalo
Lalo
Godwin Kpoton, brodelinekpot@gmail.com
- Recruiting
Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB) (Centers for Detection and Treatment of Buruli ulcer), Pobè
Pobè
Ronald Gnimavo, ronaldgnimavo@gmail.com
About this study
Official title: Beta-Lactam Containing Regimen for the Shortening of Buruli Ulcer Disease Therapy: Comparison of 8 Weeks Standard Therapy (Rifampicin Plus Clarithromycin) vs. 4 Weeks Standard Plus Amoxicillin/Clavulanate Therapy [RC8 vs. RCA4]
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.
Read more
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
- Being tested
- Standard [RC8]: rifampicin plus clarithromycin (RC) therapy for 8 weeks., Investigational [RCA4]: standard (RC) plus amoxicillin/clavulanate (A) for 4 weeks.
- Keywords
- Buruli ulcer, Neglected tropical disease, Treatment shortening, Drug combination, Amoxicillin/clavulanate, Clinical trial, Pharmacokinetic analysis, Bacterial clearance study
- Medical subject headings
- Buruli Ulcer, Neglected Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
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.
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.
| Study group | Role | What they receive |
|---|---|---|
| RC8, Rifampicin plus Clarithromycin for 8 weeks | Active comparator | Rifampicin plus Clarithromycin (RC) therapy for 8 weeks Receives: 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. Receives: Drug: Investigational [RCA4]: standard (RC) plus amoxicillin/clavulanate (A) for 4 weeks. |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Within 12 months of treatment initiation
Rate of median bacterial clearance among treatment arms in the bacterial clearance sub-study population
Measured: 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.
Measured: Within 12 months of treatment initiation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Dec 2021
- Study start1 Dec 2021
- Primary completion31 May 2026 (estimated)
- Study completion31 May 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (27)Papers the sponsor has linked to this study.
- Other trials for Buruli UlcerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 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.
- Masking
- None (open label)
- Enrolment
- 140 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Fundacion Agencia Aragonesa para la Investigacion y Desarrollo (ARAID)
- Sponsor type
- University, hospital or other
- Collaborators
- Universidad de Zaragoza, Fondation Raoul Follereau, Université d'Abomey-Calavi, Instituto de Salud Carlos III, Fundación Anesvad, Tres Cantos Open Lab Foundation, GlaxoSmithKline
- Responsible party
- Sponsor
- Investigators
- Santiago Ramón-García, Study director, Fundacion Agencia Aragonesa para la Investigacion y Desarrollo (ARAID)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05169554
- Sponsor's protocol ID
- TC281
- Acronym
- BLMs4BU
- Status last verified
- May 2024
- First submitted
- 22 Nov 2021
- Last updated
- 16 May 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 29642808Revill 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.
PubMed 4126917Espey 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.
PubMed 12044304Guarner 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.
PubMed 29343539Thangaraj 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.
PubMed 10660507World Health Organization. Treatment of Mycobacterium ulcerans infection. 2012
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.
PubMed 25654354Hu 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.
PubMed 26157437Omansen 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.
PubMed 30556580Ramon-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.
PubMed 27678056Arenaz-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.
PubMed 30689630Rolinson GN. Forty years of beta-lactam research. J Antimicrob Chemother. 1998 Jun;41(6):589-603. doi: 10.1093/jac/41.6.589.
PubMed 9687097Diacon 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.
PubMed 27433841Ma 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.
PubMed 20488518Ramon-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.
PubMed 21576426
Study at a glance
From the registry record, last updated by the sponsor on 16 May 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Beta-Lactam Containing Regimen for the Shortening of Buruli Ulcer Disease Therapy: Comparison of 8 Weeks Standard Therapy (Rifampicin Plus Clarithromycin) vs. 4 Weeks Standard Plus Amoxicillin/Clavulanate Therapy [RC8 vs. RCA4]
- ClinicalTrials.gov ID
- NCT05169554
- Acronym / sponsor ID
- BLMs4BU / TC281
- Conditions
- Buruli Ulcer
- Keywords
- Buruli ulcer, Neglected tropical disease, Treatment shortening, Drug combination, Amoxicillin/clavulanate, Clinical trial, Pharmacokinetic analysis, Bacterial clearance study
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 140 participants (estimated)
- Lead sponsor
- Fundacion Agencia Aragonesa para la Investigacion y Desarrollo (ARAID)University, hospital or other
- Collaborators
- Universidad de Zaragoza, Fondation Raoul Follereau, Université d'Abomey-Calavi, Instituto de Salud Carlos III, Fundación Anesvad, Tres Cantos Open Lab Foundation, GlaxoSmithKline
- Study start
- 1 Dec 2021 (actual)
- Primary completion
- 31 May 2026 (estimated)
- Study completion
- 31 May 2026 (estimated)
- First posted
- 27 Dec 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| RC8, Rifampicin plus Clarithromycin for 8 weeks | Active comparator | Drug: Standard [RC8]: rifampicin plus clarithromycin (RC) therapy for 8 weeks.Rifampicin plus Clarithromycin (RC) therapy for 8 weeks |
| RCA4, Rifampicin plus Clarithromycin plus Amoxicillin/clavulanate for 4 weeks. | Experimental | Drug: Investigational [RCA4]: standard (RC) plus amoxicillin/clavulanate (A) for 4 weeks.Rifampicin plus Clarithromycin (RC) plus Amoxicillin/clavulanate (A) for 4 weeks. |
Who may qualify
- Ages
- 5 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (1 listed)
- 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.
Key exclusion criteria (20 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Standard [RC8]: rifampicin plus clarithromycin (RC) therapy for 8 weeks.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. | Drug | RC8, Rifampicin plus Clarithromycin for 8 weeks |
| Investigational [RCA4]: standard (RC) plus amoxicillin/clavulanate (A) for 4 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. 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. | Drug | RCA4, Rifampicin plus Clarithromycin plus Amoxicillin/clavulanate for 4 weeks. |
Primary outcome
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
Time frame: 12 months after treatment initiation
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.
20 secondary outcomes
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 12 months after treatment initiation
Recurrence rate within 12 months of treatment initiation in all ITT-E and PP populations
Time frame: Within 12 months of treatment initiation
Treatment discontinuation rate in all ITT-E and PP populations
Time frame: Active comparator arm (RC8): 8 weeks; Experimental arm (RCA4): 4 weeks
Treatment compliance rate in all ITT-E and PP populations
Time frame: 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
Time frame: Within 12 months of treatment initiation
Median time to healing after treatment initiation in all ITT-E and PP populations
Time frame: 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
Time frame: Within 12 months of treatment initiation
Interval between healing and recurrence within 12 months of treatment initiation in all ITT-E and PP populations
Time frame: 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
Time frame: Within 12 months of treatment initiation
Rate of median bacterial clearance among treatment arms in the bacterial clearance sub-study population
Time frame: 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
Time frame: Within 12 months of treatment initiation
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 May 2024.
- Background: PubMed 29642808O'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.
- Background: PubMed 4126917Revill 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.
- Background: PubMed 12044304Espey 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.
- Background: PubMed 29343539Guarner 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.
- Background: PubMed 10660507Thangaraj 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.
- BackgroundWorld Health Organization. Treatment of Mycobacterium ulcerans infection. 2012
- Background: PubMed 25654354Boeree 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.
- Background: PubMed 26157437Hu 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.
- Background: PubMed 30556580Omansen 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.
- Background: PubMed 27678056Ramon-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.
- Background: PubMed 30689630Arenaz-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.
- Background: PubMed 9687097Rolinson GN. Forty years of beta-lactam research. J Antimicrob Chemother. 1998 Jun;41(6):589-603. doi: 10.1093/jac/41.6.589.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Santiago Ramón-García study director
Fundacion Agencia Aragonesa para la Investigacion y Desarrollo (ARAID)
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Standard [RC8]: rifampicin plus clarithromycin (RC) therapy for 8 weeks. and Investigational [RCA4]: standard (RC) plus amoxicillin/clavulanate (A) for 4 weeks. in people with Buruli Ulcer, run by Fundacion Agencia Aragonesa para la Investigacion y Desarrollo (ARAID) at 3 sites in Benin.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 16 May 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Benin. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Christian Johnson (0022996221132, rochchristianjohnson@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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 (time frame: 12 months after treatment initiation). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05169554, which also lists 27 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 May 2024.