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

Phase 2

Completed

• Conditions: Mycobacterium Ulcerans Infection
• Interventions: Drug: Clarithromycin Extended Release; Drug: Streptomycin intramuscular injection

• Registration Number: NCT01659437
• Lead Sponsor: University Medical Center Groningen

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 Several small observational studies (published and unpublished) have shown that a fully oral treatment is promising.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

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 Timeline

• Study First Submitted: 2012-08-02
• Study First Submitted QC: 2012-08-06
• Study First Posted: 2012-08-07
• Study Start: 2012-12
• Primary Completion: 2017-12
• Study Completion: 2018-01
• Status Verified: 2019-09
• Last Update Submitted: 2019-09-24
• Last Update Posted: 2019-09-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 310

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CR8	Clarithromycin Extended Release	Clarithromycin (C: 15 mg/kg per day, oral extended release formulation) in combination with rifampicin (10 mg/kg per day, orally) for 8 weeks
SR8	Streptomycin intramuscular injection	Streptomycin (S: 15 mg/kg per day, intramuscularly) in combination with rifampicin (R: 10 mg/kg per day, orally) for 8 weeks

Primary Outcome Measures

Name	Time	Method
healing without recurrence and without excision surgery	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

Name	Time	Method
Rate of treatment failure within 12 months of treatment initiation	12 months	proportion of treatment failure will be compared between groups
Proportion of patients with reduction in lesion surface area within 12 months of treatment initiation	12 months	if not cured, will there be a difference between groups in terms of reduction of lesion size?
Rate of paradoxical response within 12 months of treatment initiation	12 months	paradoxical responses that have occurred during BUD treatment will be compared in both treatment arms
Proportion (%) of patients with complete healing without additional surgery or relapse	12 months
Interval between healing and recurrence	12 months	if recurrences occur, there might be a difference in time between healing and recurrences between treatment groups
Time from treatment initiation to surgery if any	12months	does the timing of surgery differ between groups for the proportion of patients in whom doctors decide to operate?
Proportion of each type of surgery within 12 months of treatment initiation	12 months	We do not expect surgery but IF doctors operate, which type of surgery would doctors use, and does this differ between groups?
Proportion of patients with residual functional limitations	12 months	do treatments differ in terms of chance to develop functional limitations?
Recurrence rate within 12 months of treatment initiation	12 months	number of recurrent lesions occurring after initial healing within 12 months after start of treatment
Time taken for complete lesion healing within 12 months of treatment initiation	12 months	do lesions heal faster in one of the two treatments?
Treatment discontinuation and compliance rates	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?
Incidence of all adverse effects (AEs) within 12 months of treatment initiation	12 months	adverse effects occurring during or after treatment may be different between treatments

Trial Locations

Locations (5)

Agogo Presbyterian Hospital; 🇬🇭 Agogo, Ghana

Dunkwa Government Hospital; 🇬🇭 Dunkwa, Ghana

Nkawie-Toase Government Hospital; 🇬🇭 Nkawie Panyin, Ghana

Tepa Government Hosital; 🇬🇭 Tepa, Ghana

Pobè Treatment Center; 🇧🇯 Pobè, Benin