Beta-Lactam Containing Regimen for the Shortening of Buruli Ulcer Disease Therapy
NCT ID: NCT05169554
Last Updated: 2024-05-16
Study Results
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Basic Information
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RECRUITING
PHASE2
140 participants
INTERVENTIONAL
2021-12-01
2026-05-31
Brief Summary
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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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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
* 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.
TREATMENT
NONE
Study Groups
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RC8, Rifampicin plus Clarithromycin for 8 weeks
Rifampicin plus Clarithromycin (RC) therapy for 8 weeks
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.
RCA4, Rifampicin plus Clarithromycin plus Amoxicillin/clavulanate for 4 weeks.
Rifampicin plus Clarithromycin (RC) plus Amoxicillin/clavulanate (A) for 4 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.
Interventions
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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.
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.
Eligibility Criteria
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Inclusion Criteria
Exclusion Criteria
* 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.
* 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.
5 Years
70 Years
ALL
No
Sponsors
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Universidad de Zaragoza
OTHER
Fondation Raoul Follereau
UNKNOWN
Université d'Abomey-Calavi
OTHER
Instituto de Salud Carlos III
OTHER_GOV
Fundación Anesvad
UNKNOWN
Tres Cantos Open Lab Foundation
UNKNOWN
GlaxoSmithKline
INDUSTRY
Fundacion Agencia Aragonesa para la Investigacion y Desarrollo (ARAID)
OTHER
Responsible Party
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Principal Investigators
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Santiago Ramón-García
Role: STUDY_DIRECTOR
Fundacion Agencia Aragonesa para la Investigacion y Desarrollo (ARAID)
Locations
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Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB) (Centers for Detection and Treatment of Buruli ulcer), Allada
Allada, , Benin
Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB) (Centers for Detection and Treatment of Buruli ulcer), Lalo
Lalo, , Benin
Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB) (Centers for Detection and Treatment of Buruli ulcer), Pobè
Pobè, , Benin
Countries
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Central Contacts
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Facility Contacts
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References
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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.
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Other Identifiers
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TC281
Identifier Type: -
Identifier Source: org_study_id
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