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

  • STATUS
    Recruiting
  • End date
    Nov 30, 2024
  • participants needed
    140
  • sponsor
    Fundacion Agencia Aragonesa para la Investigacion y Desarrollo (ARAID)
Updated on 8 January 2022

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.

Details
Condition Buruli Ulcer
Treatment Standard [RC8]: rifampicin plus clarithromycin (RC) therapy for 8 weeks., Investigational [RCA4]: standard (RC) plus amoxicillin/clavulanate (A) for 4 weeks.
Clinical Study IdentifierNCT05169554
SponsorFundacion Agencia Aragonesa para la Investigacion y Desarrollo (ARAID)
Last Modified on8 January 2022

Eligibility

Yes No Not Sure

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

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
-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)
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