Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202209521256638 Date of Approval: 19/09/2022
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Shortening Buruli Ulcer treatment: WHO recommended vs. a novel beta-lactam-containing therapy - Phase III evaluation in West Africa
Official scientific title Shortening Buruli Ulcer treatment: WHO recommended vs. a novel beta-lactam-containing therapy - Phase III evaluation in West Africa
Brief summary describing the background and objectives of the trial Buruli ulcer (BU), caused by Mycobacterium ulcerans (Mul), 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. Wound healing can take up to one year. Compliance to treatment 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 Mul. Amoxicillin/clavulanate is oral, suitable for treatment in adults and children, and readily available with an established clinical safety profile. We propose a multi-country, randomized, controlled, open label, non-inferiority Phase III clinical trial in Ghana, Côte d’Ivoire and Togo 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. The primary efficacy outcome will be cure rate, i.e., lesion healing without recurrence and without excision surgery 12 months after start of treatment. 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, for which rifampicin is the cornerstone drug in therapy.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) BLMs4BU
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied Buruli ulcer
Purpose of the trial Treatment: Drugs
Anticipated trial start date 01/12/2022
Actual trial start date
Anticipated date of last follow up 30/11/2025
Actual Last follow-up date
Anticipated target sample size (number of participants) 174
Actual target sample size (number of participants) 174
Recruitment status Recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Randomised Permuted block randomization Central randomisation by phone/fax Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Control Group Standard RC8 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 and CLA, 7.5 mg/kg. 8 weeks Rifampicin plus clarithromycin (RC) therapy for 8 weeks 87 Active-Treatment of Control Group
Experimental Group Investigational RCA4 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 and CLA, 7.5 mg/kg. 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. 4 weeks Standard (Rifampicin and clarithromycin) plus amoxicillin/clavulanate (A) for 4 weeks. 87
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
- All patients (both genders) with a new “Very Likely” or “Likely” (as per World Health Organisation, WHO, scoring criteria) clinical BU diagnosis (all categories: I, II, III).(The WHO clinical diagnosis would be supported, as agreed, by the trial and reviewed by the local study technical expert panel.) - Normal ECG (QTc ≤ 450 ms) at baseline that give informed consent will be included in the study. • 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 BU with at least one of the study drugs within 1 year before recruitment. • Patients with diagnosis of 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 amoxicillin or 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 before recruitment. • Patients currently receiving treatment with any drug 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 taking other medication known to prolong the QTc interval, such as quinolones. In this case, if suspected of BU disease, patients will be treated according to established local guidelines, i.e. with rifampicin and streptomycin for 8 weeks, if available, or will be referred for surgical treatment. • Patients unable to take oral medications 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 i Adolescent: 13 Year-18 Year,Adult: 19 Year-44 Year,Aged: 65+ Year(s),Child: 6 Year-12 Year,Middle Aged: 45 Year(s)-64 Year(s) 5 Year(s) 70 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 30/09/2022 Comite National dEthique des Sciences de la Vie de Cote dIvoire
Ethics Committee Address
Street address City Postal code Country
CHU de Cocody Institut Pasteur de Cote dIvoire Abidjan-Cocody 82V3 MQ3 Cote Divoire
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 03/10/2022 Ghana Health Service Ethics Review Committee
Ethics Committee Address
Street address City Postal code Country
GHS Headquarters Accra Accra MB190 Ghana
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 12/10/2022 Comite de Bioethique pour la Recherche en Sante CBRS
Ethics Committee Address
Street address City Postal code Country
Ministere de la Sante, Direction des Pharmacies, Angle avenue Sarakawa et avenue du 2 Fevrier Lome BP 386 Togo
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome 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-positive population. The PP PCR-positive population includes those randomized patients with a WHO clinical diagnosis of “Very Likely BU” or “Likely BU”, PCR-positive and with no major violations of the protocol. 12 months after treatment initiation
Secondary Outcome Rate of complete lesion healing without recurrence and without excision surgery, 12 months after start of treatment in the ITT-E PCR-positive, PP CD, and ITT-E CD populations. - Intention To Treat Exposed (ITT-E) PCR-positive population. The ITT-E PCR-positive population includes those randomized patients with a clinical diagnosis of “Very Likely BU” or “Likely BU”, PCR-positive 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-positive and PCR-negative. - 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-positive and PCR-negative and major violators of the protocol. 12 months after treatment initiation
Secondary Outcome 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) population. This population will consist of all randomized patients, with a clinical diagnosis of “Very Likely BU” or “Likely BU” (WHO), 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) population.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
Secondary Outcome Recurrence rate within 12 months of treatment initiation in all ITT-E and PP populations. - Intention-to-Treat Exposed (ITT-E) population. This population will consist of all randomized patients, with a clinical diagnosis of “Very Likely BU” or “Likely BU” (WHO), 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) population. 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
Secondary Outcome Treatment discontinuation rate in all ITT-E and PP populations. - Intention-to-Treat Exposed (ITT-E) population. This population will consist of all randomized patients, with a clinical diagnosis of “Very Likely BU” or “Likely BU” (WHO), 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) population. This population will consist of subjects in the ITT-E population who complete the study and are not major protocol violators. Control group standard, RC8: 8 weeks. Experimental arm, RCA4: 4 weeks
Secondary Outcome Treatment compliance rate in all ITT-E and PP populations. - Intention-to-Treat Exposed (ITT-E) population. This population will consist of all randomized patients, with a clinical diagnosis of “Very Likely BU” or “Likely BU” (WHO), 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) population. This population will consist of subjects in the ITT-E population who complete the study and are not major protocol violators. Control group standard, RC8: 8 weeks. Experimental arm, RCA4: 4 weeks.
Secondary Outcome Rate of paradoxical response within 12 months of treatment initiation in all ITT-E and PP populations. - Intention-to-Treat Exposed (ITT-E) population. This population will consist of all randomized patients, with a clinical diagnosis of “Very Likely BU” or “Likely BU” (WHO), 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) population. 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
Secondary Outcome Median time to healing after treatment initiation in all ITT-E and PP populations. - Intention-to-Treat Exposed (ITT-E) population. This population will consist of all randomized patients, with a clinical diagnosis of “Very Likely BU” or “Likely BU” (WHO), 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) population. 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
Secondary Outcome 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) population. This population will consist of all randomized patients, with a clinical diagnosis of “Very Likely BU” or “Likely BU” (WHO), 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) population. 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
Secondary Outcome Interval between healing and recurrence within 12 months of treatment initiation in all ITT-E and PP populations. - Intention-to-Treat Exposed (ITT-E) population. This population will consist of all randomized patients, with a clinical diagnosis of “Very Likely BU” or “Likely BU” (WHO), 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) population. 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
Secondary Outcome 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) population. This population will consist of all randomized patients, with a clinical diagnosis of “Very Likely BU” or “Likely BU” (WHO), 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) population. 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
Secondary Outcome 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) population. This population will consist of all randomized patients, with a clinical diagnosis of “Very Likely BU” or “Likely BU” (WHO), 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) population. 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
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Jacobu Government Hospital Amansie Central Jacobu Ghana
Nkawie Hospital Nkawie Road Toase Ghana
Centre Hospitalier Regional de Divo Divo Divo Cote Divoire
Centre Hospitalier Regional Tsevie Tsevie Tsevie Togo
FUNDING SOURCES
Name of source Street address City Postal code Country
Anesvad Foundation Henao Kalea Bilbao Spain
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor University of Zaragoza Pedro Cerbuna 12 Zaragoza 50009 Spain University
COLLABORATORS
Name Street address City Postal code Country
Research and Development Agency of Aragon ARAID Av. de Ranillas Zaragoza Spain
Kwame Nkrumah University of Science and Technology KNUST Accra Rd Kumasi Ghana
Ghana Health Service Accra Accra Ghana
Programme National des Maladies Tropicales Negligees PNMTN Togo Lome Lome Togo
Programme National de Lutte Contre l Ulcere de Buruli PNLUB Cote DIvoire Abidjan Abidjan Cote Divoire
Anesvad Foundation Henao Kalea Bilbao Spain
Fondation Raoul Follereau FRF 31 rue de Dantzig Paris France
DAHW Deutsche Lepra und Tuberkulosehilfe e V Raiffeisenstrase 3 Wurzburg Germany
Instituto de Salud Carlos III Sinesio Delgado 10 Madrid Spain
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Santiago Ramon Garcia santiramon@unizar.es +034976761693 Departament of Microbiology, Faculty of Medicine, Domingo Miral Sn
City Postal code Country Position/Affiliation
Zaragoza Spain ARAID University of Zaragoza Investigator
Role Name Email Phone Street address
Principal Investigator Richard Odame Phillips phillips@kccr.de +233322060511 Kumasi Centre for Collaborative Research in Tropical medicine KCCR, Kwame Nkrumah University of Science and Technology KNUST, South-end, Asuogya Rd
City Postal code Country Position/Affiliation
Kumasi Ghana Scientific Director Kumasi Centre for Collaborative Research in Tropical medicine KCCR Kwame Nkrumah University of Science and Technology KNUST
Role Name Email Phone Street address
Principal Investigator Denis Agbenyigan Yawovi Gadah denis.gadah@dahw.org +22822232230 DAHW Deutsche Lepra und Tuberkulosehilfe e V , Avenue De la Providence, Centre Dermatologique Gbossime
City Postal code Country Position/Affiliation
Lome Togo Program Director DAHW Deutsche Lepra und Tuberkulosehilfe e V
Role Name Email Phone Street address
Principal Investigator Mamadou Kaloga kaloganas@yahoo.fr +22507845645 C.H.U de Treichville, 14 B.P. 1960 Abidjan 14
City Postal code Country Position/Affiliation
Abidjan Cote Divoire Professeur Titulaire Programme National de Lutte Contre l Ulcere de Buruli
Role Name Email Phone Street address
Principal Investigator Israel Cruz Mata cruzi@isciii.es +34918222312 National School of Public Health, Instituto de Salud Carlos III, Sinesio Delgado 8
City Postal code Country Position/Affiliation
Madrid Spain Head International Health Department National School of Public Health Instituto de Salud Carlos III
Role Name Email Phone Street address
Public Enquiries Santiago Ramon Garcia santiramon@unizar.es +34976761693 Departament of Microbiology, Faculty of Medicine, Domingo Miral Sn
City Postal code Country Position/Affiliation
Zaragoza Spain Investigator ARAID University of Zaragoza
Role Name Email Phone Street address
Scientific Enquiries Santiago Ramon Garcia santiramon@unizar.es +34976761693 Departament of Microbiology, Faculty of Medicine, Domingo Miral sn
City Postal code Country Position/Affiliation
Zaragoza Spain Investigator ARAID University of Zaragoza
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Individual participant data after de-identifcation and trial tools including study protocol, statistical analysis plan, and analytic code will be made available 1 month after publication of the article reporting the main fndings of this trial, with no end date, to researchers who provide a methodologically sound proposal, upon signature of a data access agreement. Proposals should be directed to the corresponding author. Analytic Code,Statistical Analysis Plan,Study Protocol 1 month after publication of the article reporting the main fndings of this trial, with no end date, to researchers who provide a methodologically sound proposal, upon signature of a data access agreement. Proposals should be directed to the corresponding author.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information