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

Information source: University Medical Center Groningen
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Mycobacterium Ulcerans Infection

Intervention: Clarithromycin Extended Release (Drug); Streptomycin intramuscular injection (Drug)

Phase: Phase 2/Phase 3

Status: Recruiting

Sponsored by: University Medical Center Groningen

Official(s) and/or principal investigator(s):
Tjip S van der Werf, MD, PhD, Principal Investigator, Affiliation: University of Groningen, University Medical Centre Groningen
Richard O Phillips, MD, PhD, Study Director, Affiliation: Komfo Anokye Teaching Hospital, Kwame Nkrumah University of Science & Technology, Kumasi, Ghana
Annick Chauty, MD, Study Director, Affiliation: Pobè Health Centre, Pobè, Bénin
Kingsley B Asiedu, MD, MPH, Study Chair, Affiliation: WHO, GBUI, Geneva, Switserland

Overall contact:
Tjip S van der Werf, MD, PhD, Phone: 0031623833846 / 0031503611501, Email: t.s.van.der.werf@umcg.nl

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 Several small observational studies (published and unpublished) have shown that a fully oral treatment is promising.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

Clinical Details

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 design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: healing without recurrence and without excision surgery

Secondary outcome:

Recurrence rate within 12 months of treatment initiation

Rate of treatment failure within 12 months of treatment initiation

Rate of paradoxical response within 12 months of treatment initiation

Proportion of patients with reduction in lesion surface area within 12 months of treatment initiation

Time taken for complete lesion healing within 12 months of treatment initiation

Proportion (%) of patients with complete healing without additional surgery or relapse

Interval between healing and recurrence

Proportion of each type of surgery within 12 months of treatment initiation

Time from treatment initiation to surgery if any

Proportion of patients with residual functional limitations

Treatment discontinuation and compliance rates

Incidence of all adverse effects (AEs) within 12 months of treatment initiation

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

Eligibility

Minimum age: 5 Years. Maximum age: N/A. Gender(s): Both.

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

Locations and Contacts

Tjip S van der Werf, MD, PhD, Phone: 0031623833846 / 0031503611501, Email: t.s.van.der.werf@umcg.nl

Pobè Treatment Center, Pobè, Benin; Recruiting
Annick Chauty, MD, Email: achauty@gmail.com
Marie Françoise Ardent
Annick Chauty, MD, Sub-Investigator

Agogo Presbyterian Hospital, Agogo, Ghana; Recruiting
William Thompson, MD, Email: thomasmnsh@yahoo.com
Kabiru M Abass, Phone: 00233244533129, Email: abass@agogopresbyhospital.org
William Thompson, MD, Sub-Investigator

Dunkwa Government Hospital, Dunkwa, Ghana; Recruiting
Godfred Sarpong, MD, Email: kobbymed@yahoo.com
Kojo Lindsey, MD
Godfred Sarpong, MD, Sub-Investigator

Nkawie-Toase Government Hospital, Nkawie, Ghana; Recruiting
Peter Awuah, MD, Email: pcawuah@yahoo.com
Wilson Tuah, Email: tuah_wilson@yahoo.com
Peter Awuah, MD, Sub-Investigator

Tepa Government Hosital, Tepa, Ghana; Recruiting
Mark Forson, MD
Nana A Bobi
Mark Forson, MD, Sub-Investigator

Additional Information

WHO Buruli ulcer website

Related 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.

Starting date: December 2012
Last updated: January 2, 2015

Page last updated: August 23, 2015

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