WHO Drug Study for Buruli Ulcer - Comparison of SR8 and CR8

• ClinicalTrials.gov Identifier: NCT01659437
• Recruitment Status: Completed
• First Posted: August 7, 2012
• Last Update Posted: September 26, 2019
• Sponsor: University Medical Center Groningen
• Collaborators: University of Groningen; Faculté de Médecine P&M Curie, Paris-6 - Site Pitié-Salpêtrière, France; Drugs for Neglected Diseases; World Alliance for Wound and Lymphoedema Care, Switzerland; Inserm U892/CNRS 699 bactériologie, Université CHU;Angers- IRIS France; Institute of Tropical Medicine, Antwerp, Belgium; National Buruli ulcer Control Programme, Ghana Health Service, Accra, Ghana; School of Med Sciences, Kwame Nkrumah Univ of Sci & Techn, Kumasi, Ghana; Komfo Anokye Teaching Hospital; Kumasi Center for Collaborative Research into Tropical Medicine, Kumasi, Ghana; Plastic Surgery and Burns Centre, Korle-Bu Teaching Hospital, Accra, Ghana; University of Ghana; Noguchi Memorial Institute of Medical Research, Accra, Ghana; Program Nat de Lutte contre la Lèpre et l'UB;Ulcère de Buruli, Cotonou, Benin
• Information provided by (Responsible Party): Tjip van der Werf, University Medical Center Groningen

Study Description

Brief Summary:

This is a WHO-sponsored trial.

Combination therapy with streptomycin and rifampicin has been the standard antibiotic treatment for M. ulcerans infection since 2004. In March 2010, a WHO Technical Advisory Group recommended that a trial be carried out to develop a fully oral treatment for the disease. Although the current treatment is effective, injection with streptomycin is a problem. Several small observational studies (published and unpublished) have shown that a fully oral treatment is promising.

This WHO sponsored study will be a randomized, controlled open label non-inferiority phase II/III, multi-centre trial (1 centre in Benin and 4 centres in Ghana), with two parallel treatment groups. The ultimate goal is to search for an effective alternative treatment to the current standard WHO-recommended therapy for all forms of Buruli ulcer, which includes injections of streptomycin with inherent logistic, operational and safety disadvantages.

Financial and material support:

1. American Leprosy Missions, USA
2. Raoul Follereau Foundation, France
3. MAP International, USA
4. Sanofi, France
5. 7th Framework Programme of the European Union: BuruliVac project (241500)
6. Aranz Medical Limited, New Zealand

Condition or disease	Intervention/treatment	Phase
Mycobacterium Ulcerans Infection	Drug: Clarithromycin Extended Release; Drug: Streptomycin intramuscular injection	Phase 2; Phase 3

Detailed Description:

A total of 415 patients in whom Buruli ulcer has been clinically diagnosed will be included in the study, which will consist of 332 cases of category I and II Buruli ulcers (<10 cm) confirmed by polymerase chain reaction (PCR), plus 83 non PCR-confirmed Buruli ulcers. Patients will be randomized to receive treatment with the two antibiotic regimens as follows:

(i) Regimen I (SR8): 15 mg/kg streptomycin per day intramuscular injection for 8 weeks plus 10 mg/kg per day oral rifampicin for 8 weeks; (ii) Regimen II (CR8): 15 mg/kg per day oral extended-release clarithromycin for 8 weeks plus 10 mg/kg per day oral rifampicin for 8 weeks.

Assessments before, during and after the course of antibiotic treatment will include full medical history, clinical assessments and monitoring of vital signs, assessment of the lesion, laboratory investigations, hearing test, electrocardiogram, pregnancy test, voluntary HIV counseling and testing, and functional limitation assessment. The primary efficacy parameters are healing without recurrence and without excision surgery 12 months after the start of treatment.

The primary endpoint will be assessed by a panel of experts unaware of the treatment ('single blinded' for treatment allocation).

Statistician:

Mr Bruno Scherrer, Consultant, Drugs for Neglected Diseases initiative, Switzerland

Data Management:

Mr Raymond Omollo, Drugs for Neglected Diseases initiative (DNDi) Africa

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 310 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized Controlled Trial Comparing Efficacy of 8 Weeks Treatment With Clarithromycin and Rifampicin Versus Streptomycin and Rifampicin for Buruli Ulcer (M. Ulcerans Infection)
• Study Start Date: December 2012
• Actual Primary Completion Date: December 2017
• Actual Study Completion Date: January 2018

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: SR8; Streptomycin (S: 15 mg/kg per day, intramuscularly) in combination with rifampicin (R: 10 mg/kg per day, orally) for 8 weeks	Drug: Streptomycin intramuscular injection; daily intramuscular drug injection
Experimental: CR8; Clarithromycin (C: 15 mg/kg per day, oral extended release formulation) in combination with rifampicin (10 mg/kg per day, orally) for 8 weeks	Drug: Clarithromycin Extended Release; oral administration of Clarithromycin extended release

Outcome Measures

Primary Outcome Measures :

1. healing without recurrence and without excision surgery [ Time Frame: 12 months after start of treatment ]
   complete epithelialisation and absence of swelling at the site of original infection, measured 12 months after start of treatment; lesion site will be examined by inspection and palpation, and documented by digital camera; digital images will be examined by panel of wound experts unaware of treatment allocation

Secondary Outcome Measures :

1. Recurrence rate within 12 months of treatment initiation [ Time Frame: 12 months ]
   number of recurrent lesions occurring after initial healing within 12 months after start of treatment
2. Rate of treatment failure within 12 months of treatment initiation [ Time Frame: 12 months ]
   proportion of treatment failure will be compared between groups
3. Rate of paradoxical response within 12 months of treatment initiation [ Time Frame: 12 months ]
   paradoxical responses that have occurred during BUD treatment will be compared in both treatment arms
4. Proportion of patients with reduction in lesion surface area within 12 months of treatment initiation [ Time Frame: 12 months ]
   if not cured, will there be a difference between groups in terms of reduction of lesion size?
5. Time taken for complete lesion healing within 12 months of treatment initiation [ Time Frame: 12 months ]
   do lesions heal faster in one of the two treatments?
6. Proportion (%) of patients with complete healing without additional surgery or relapse [ Time Frame: 12 months ]
7. Interval between healing and recurrence [ Time Frame: 12 months ]
   if recurrences occur, there might be a difference in time between healing and recurrences between treatment groups
8. Proportion of each type of surgery within 12 months of treatment initiation [ Time Frame: 12 months ]
   We do not expect surgery but IF doctors operate, which type of surgery would doctors use, and does this differ between groups?
9. Time from treatment initiation to surgery if any [ Time Frame: 12months ]
   does the timing of surgery differ between groups for the proportion of patients in whom doctors decide to operate?
10. Proportion of patients with residual functional limitations [ Time Frame: 12 months ]
    do treatments differ in terms of chance to develop functional limitations?
11. Treatment discontinuation and compliance rates [ Time Frame: 8 weeks ]
    one treatment might be better tolerated than the other; do treatments differ in terms of adherence problems, and do participants in any of these two treatment arms differ in terms of the chance to discontinue the treatment?
12. Incidence of all adverse effects (AEs) within 12 months of treatment initiation [ Time Frame: 12 months ]
    adverse effects occurring during or after treatment may be different between treatments

Eligibility Criteria

• Ages Eligible for Study: 5 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria:

• All patients (both genders) with a clinical diagnosis of BUD (categories: I and II, cross-sectional diameter ≤ 10cm) as agreed by study site treatment team led by the lead clinicians

Exclusion criteria:

1. Patients with lesion sizes >10cm in cross-sectional diameter
2. Children < 5 years, or < 20 kilograms body weight
3. Pregnancy (self-reported, clinically diagnosed, or urine test (beta-hCG) positive
4. Patients with previous treatment of Buruli ulcer, tuberculosis or leprosy with at least one of the study drugs (rifampicin, streptomycin, clarithromycin)
5. Patients with history of hypersensitivity to rifampicin and/or streptomycin and/or clarithromycin
6. Patients with previous treatment with macrolide or quinolone antibiotics, or antituberculosis medication, or immuno-modulatory drugs including corticosteroids within one month
7. Patients with current treatment with any drugs likely to interact with the study medication, e.g, anticoagulants, cyclosporin, phenytoin, and phenobarbitone. Users of oral contraceptives should be notified that such contraceptive is less reliable if taken with rifampicin; alternative (mechanical) contraceptive methods will be discussed with the study participant
8. Patients with co-infection with HIV
9. Patients with history or having current clinical signs of ascites, jaundice, partial or complete deafness, myasthenia gravis, renal dysfunction (known or suspected), diabetes mellitus, and severe immune compromise (e.g., immunosuppressive drugs after organ transplant), or evidence of (previous) tuberculosis, Buruli ulcer or leprosy; or terminal illness (e.g., metastasized cancer)
10. Patients who are unable to take oral medication or having gastrointestinal disease likely to interfere with drug absorption
11. Patients with known or suspected bowel strictures who cannot tolerate macrolide antibiotics such as clarithromycin
12. Patients with mental condition, including addiction with substance abuse (alcohol, qat, etc) likely to interfere with possibility to comply with the study protocol
13. Patients who are not willing to give informed pre-consent, and consent (patient and/or parent/legal representative), or withdrawal of consent

Contacts and Locations

Locations

Benin

Pobè Treatment Center

Pobè, Benin

Ghana

Agogo Presbyterian Hospital

Agogo, Ghana

Dunkwa Government Hospital

Dunkwa, Ghana

Nkawie-Toase Government Hospital

Nkawie Panyin, Ghana

Tepa Government Hosital

Tepa, Ghana

Sponsors and Collaborators

University Medical Center Groningen

University of Groningen

Faculté de Médecine P&M Curie, Paris-6 - Site Pitié-Salpêtrière, France

Drugs for Neglected Diseases

World Alliance for Wound and Lymphoedema Care, Switzerland

Inserm U892/CNRS 699 bactériologie, Université CHU;Angers- IRIS France

Institute of Tropical Medicine, Antwerp, Belgium

National Buruli ulcer Control Programme, Ghana Health Service, Accra, Ghana

School of Med Sciences, Kwame Nkrumah Univ of Sci & Techn, Kumasi, Ghana

Komfo Anokye Teaching Hospital

Kumasi Center for Collaborative Research into Tropical Medicine, Kumasi, Ghana

Plastic Surgery and Burns Centre, Korle-Bu Teaching Hospital, Accra, Ghana

University of Ghana

Noguchi Memorial Institute of Medical Research, Accra, Ghana

Program Nat de Lutte contre la Lèpre et l'UB;Ulcère de Buruli, Cotonou, Benin

Investigators

• Principal Investigator: Tjip S van der Werf, MD, PhD; University of Groningen, University Medical Centre Groningen
• Study Director: Richard O Phillips, MD, PhD; Komfo Anokye Teaching Hospital, Kwame Nkrumah University of Science & Technology, Kumasi, Ghana
• Study Director: Annick Chauty, MD; Pobè Health Centre, Pobè, Bénin
• Study Chair: Kingsley B Asiedu, MD, MPH; WHO, GBUI, Geneva, Switserland

More Information

Additional Information:

WHO Buruli ulcer website 

Publications:

Nienhuis WA, Stienstra Y, Thompson WA, Awuah PC, Abass KM, Tuah W, Awua-Boateng NY, Ampadu EO, Siegmund V, Schouten JP, Adjei O, Bretzel G, van der Werf TS. Antimicrobial treatment for early, limited Mycobacterium ulcerans infection: a randomised controlled trial. Lancet. 2010 Feb 20;375(9715):664-72. doi: 10.1016/S0140-6736(09)61962-0. Epub 2010 Feb 3.

Chauty A, Ardant MF, Marsollier L, Pluschke G, Landier J, Adeye A, Goundoté A, Cottin J, Ladikpo T, Ruf T, Ji B. Oral treatment for Mycobacterium ulcerans infection: results from a pilot study in Benin. Clin Infect Dis. 2011 Jan 1;52(1):94-6. doi: 10.1093/cid/ciq072.

Gordon CL, Buntine JA, Hayman JA, Lavender CJ, Fyfe JA, Hosking P, Starr M, Johnson PD. All-oral antibiotic treatment for buruli ulcer: a report of four patients. PLoS Negl Trop Dis. 2010 Nov 30;4(11):e770. doi: 10.1371/journal.pntd.0000770.

O'Brien DP, McDonald A, Callan P, Robson M, Friedman ND, Hughes A, Holten I, Walton A, Athan E. Successful outcomes with oral fluoroquinolones combined with rifampicin in the treatment of Mycobacterium ulcerans: an observational cohort study. PLoS Negl Trop Dis. 2012 Jan;6(1):e1473. doi: 10.1371/journal.pntd.0001473. Epub 2012 Jan 17.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Phillips RO, Robert J, Abass KM, Thompson W, Sarfo FS, Wilson T, Sarpong G, Gateau T, Chauty A, Omollo R, Ochieng Otieno M, Egondi TW, Ampadu EO, Agossadou D, Marion E, Ganlonon L, Wansbrough-Jones M, Grosset J, Macdonald JM, Treadwell T, Saunderson P, Paintsil A, Lehman L, Frimpong M, Sarpong NF, Saizonou R, Tiendrebeogo A, Ohene SA, Stienstra Y, Asiedu KB, van der Werf TS; study team. Rifampicin and clarithromycin (extended release) versus rifampicin and streptomycin for limited Buruli ulcer lesions: a randomised, open-label, non-inferiority phase 3 trial. Lancet. 2020 Apr 18;395(10232):1259-1267. doi: 10.1016/S0140-6736(20)30047-7. Epub 2020 Mar 12.

Converse PJ, Almeida DV, Tasneen R, Saini V, Tyagi S, Ammerman NC, Li SY, Anders NM, Rudek MA, Grosset JH, Nuermberger EL. Shorter-course treatment for Mycobacterium ulcerans disease with high-dose rifamycins and clofazimine in a mouse model of Buruli ulcer. PLoS Negl Trop Dis. 2018 Aug 13;12(8):e0006728. doi: 10.1371/journal.pntd.0006728. eCollection 2018 Aug.

• Responsible Party: Tjip van der Werf, Professor, University Medical Center Groningen
• ClinicalTrials.gov Identifier: NCT01659437
• Other Study ID Numbers: T9-370-1
• First Posted: August 7, 2012
• Last Update Posted: September 26, 2019
• Last Verified: September 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: after publication, IPD will be made available at the time of publication; enrollment is complewted with 310 participants enrolled by Dec 2017; final report submitted for publication Sept 2019
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: data analysis report as well as data in OpenClinica deposited with DNDi Regional Africa Office Nairobi

Keywords provided by Tjip van der Werf, University Medical Center Groningen:

M. ulcerans; Buruli ulcer; drug trial; clarithromycin

Additional relevant MeSH terms:

Buruli Ulcer; Infections; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Mycobacterium Infections, Nontuberculous; Skin Ulcer; Skin Diseases; Clarithromycin; Streptomycin; Anti-Bacterial Agents; Anti-Infective Agents; Protein Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors