Clinical trial NCT05169554: Beta-Lactam Containing Regimen for the Shortening of Buruli Ulcer Disease Therapy
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]
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Buruli Ulcer
Keywords: Buruli ulcer
Neglected tropical disease
Treatment shortening
Drug combination
Amoxicillin/clavulanate
Clinical trial
Pharmacokinetic analysis
Bacterial clearance study
Lead sponsor: Fundacion Agencia Aragonesa para la Investigacion y Desarrollo (ARAID)
Sponsor class: OTHER
Collaborators: name: Universidad de Zaragoza
name: Fondation Raoul Follereau
name: Université d'Abomey-Calavi
name: Instituto de Salud Carlos III
name: Fundación Anesvad
name: Tres Cantos Open Lab Foundation
name: GlaxoSmithKline
First posted: 2021-12-27
Enrollment: 140
Sex: ALL
Minimum age (years): 5
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

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.


Eligibility criteria: 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 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).

Primary outcomes:
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
timeFrame: 12 months after treatment initiation
Secondary outcomes:
measure: 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.
timeFrame: Between week 1 and week 2 after treatment initiation
measure: Derive and compare the trough concentration (Cτ) (pharmacokinetic parameter) for RIF, CLA and AMX for the two groups (RC8 and RCA4) at steady-state.
timeFrame: Between week 1 and week 2 after treatment initiation
measure: 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.
timeFrame: Between week 1 and week 2 after treatment initiation
measure: 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.
timeFrame: Between week 1 and week 2 after treatment initiation
measure: 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.
timeFrame: Between week 1 and week 2 after treatment initiation
measure: 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.
timeFrame: Between week 1 and week 2 after treatment initiation
measure: 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.
timeFrame: Between week 1 and week 2 after treatment initiation
measure: 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.
timeFrame: Between week 1 and week 2 after treatment initiation
measure: 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
timeFrame: 12 months after treatment initiation
measure: 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
timeFrame: 12 months after treatment initiation
measure: Recurrence rate within 12 months of treatment initiation in all ITT-E and PP populations
timeFrame: Within 12 months of treatment initiation
measure: Treatment discontinuation rate in all ITT-E and PP populations
timeFrame: Active comparator arm (RC8): 8 weeks; Experimental arm (RCA4): 4 weeks
measure: Treatment compliance rate in all ITT-E and PP populations
timeFrame: Active comparator arm (RC8): 8 weeks; Experimental arm (RCA4): 4 weeks
measure: Rate of paradoxical response within 12 months of treatment initiation in all ITT-E and PP populations
timeFrame: Within 12 months of treatment initiation
measure: Median time to healing after treatment initiation in all ITT-E and PP populations
timeFrame: Within 12 months of treatment initiation until the date of healing time
measure: Proportion of patients with reduction in lesion surface area within 12 months of treatment initiation in all ITT-E and PP populations
timeFrame: Within 12 months of treatment initiation
measure: Interval between healing and recurrence within 12 months of treatment initiation in all ITT-E and PP populations
timeFrame: Within 12 months of treatment initiation
measure: 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
timeFrame: Within 12 months of treatment initiation
measure: Rate of median bacterial clearance among treatment arms in the bacterial clearance sub-study population
timeFrame: Within 8 weeks or 14 weeks after treatment initiation according to the healing time
measure: 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
timeFrame: Within 12 months of treatment initiation
Other outcomes:
Locations:
city: Allada
country: Benin
facility: Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB) (Centers for Detection and Treatment of Buruli ulcer), Allada
city: Lalo
country: Benin
facility: Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB) (Centers for Detection and Treatment of Buruli ulcer), Lalo
city: Pobè
country: Benin
facility: Centre de Dépistage et de Traitement de l'Ulcère de Buruli (CDTUB) (Centers for Detection and Treatment of Buruli ulcer), Pobè
Study officials:
affiliation: Fundacion Agencia Aragonesa para la Investigacion y Desarrollo (ARAID)
name: Santiago Ramón-García
role: STUDY_DIRECTOR
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