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

Study Overview
=================
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.

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]

Conditions
-----------------
Buruli Ulcer

Intervention / Treatment
-----------------
* Drug: Standard [RC8]: rifampicin plus clarithromycin (RC) therapy for 8 weeks.
* Drug: Investigational [RCA4]: standard (RC) plus amoxicillin/clavulanate (A) for 4 weeks.


Participation Criteria
=================
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).

Ages Eligible for Study
-----------------
Minimum Age: 5 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: RC8, Rifampicin plus Clarithromycin for 8 weeks<br>Rifampicin plus Clarithromycin (RC) therapy for 8 weeks | Drug: Standard [RC8]: rifampicin plus clarithromycin (RC) therapy for 8 weeks.<br>* 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.<br>|
| Experimental: RCA4, Rifampicin plus Clarithromycin plus Amoxicillin/clavulanate for 4 weeks.<br>Rifampicin plus Clarithromycin (RC) plus Amoxicillin/clavulanate (A) for 4 weeks. | Drug: Investigational [RCA4]: standard (RC) plus amoxicillin/clavulanate (A) for 4 weeks.<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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 (Cτ) (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 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Buruli ulcer, Neglected tropical disease, Treatment shortening, Drug combination, Amoxicillin/clavulanate, Clinical trial, Pharmacokinetic analysis, Bacterial clearance study