A Phase 2 interventional study of Standard [RC8]: rifampicin plus clarithromycin (RC) therapy for 8 weeks. and Investigational [RCA4]: standard (RC) plus amoxicillin/clavulanate (A) for 4 weeks. in Buruli Ulcer, sponsored by Fundacion Agencia Aragonesa para la Investigacion y Desarrollo (ARAID). Status unknown at 3 sites in Benin. Open to participants aged 5 Years to 70 Years. Per ClinicalTrials.gov, last updated 2024-05-16.
Sponsored by Fundacion Agencia Aragonesa para la Investigacion y Desarrollo (ARAID) · Phase 2, Interventional, and Treatment
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.
41 studies on the registry are indexed under Neglected Diseases; 8 are open to participants now.
This study's planned enrollment of 140 is below the median of 166 across 31 interventional studies indexed under Neglected Diseases.
Browse Neglected Diseases studies →This is the only study on the registry with Fundacion Agencia Aragonesa para la Investigacion y Desarrollo (ARAID) as lead sponsor.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
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 (ECG) at baseline giving will be included in the study, as agreed by study site treatment team led by the lead clinicians.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A recording of the heart’s electrical activity, taken with stickers on the chest, arms and legs. It takes a few minutes and does not hurt.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
The other ingredients in a medicine besides the active drug, such as fillers, colours or preservatives.
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.
The study may name a correction formula and a limit in milliseconds, often around 450–480.
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
ECG (electrocardiogram)
A recording of the heart’s electrical activity, taken with stickers on the chest, arms and legs. It takes a few minutes and does not hurt.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Excipients
The other ingredients in a medicine besides the active drug, such as fillers, colours or preservatives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
QT and QTc
On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.
The study may name a correction formula and a limit in milliseconds, often around 450–480.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Cancer (malignancy)
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Clinically significant
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Rifampicin plus Clarithromycin (RC) therapy for 8 weeks
Drug: Standard [RC8]: rifampicin plus clarithromycin (RC) therapy for 8 weeks.
Rifampicin plus Clarithromycin (RC) plus Amoxicillin/clavulanate (A) for 4 weeks.
Drug: Investigational [RCA4]: standard (RC) plus amoxicillin/clavulanate (A) for 4 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.
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.
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.
Time frame: 12 months after treatment initiation
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.
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.
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.
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.
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.
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.
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
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.
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
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
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
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.
Time frame: 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.
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
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.
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
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.
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
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.
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
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.
Time frame: Within 12 months of treatment initiation
Plan to share: No
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