BURULICO Drug Trial Study Protocol: RCT SR8/SR4+CR4, GHANA

Buruli Ulcer Clinical Trial

— BURULICO  

Official title:

Randomised Trial for Early Lesions Caused by M. Ulcerans - Comparison Between 8 Weeks Streptomycin and Rifampicin (SR), or 4 Weeks SR Followed by 4 Weeks R Plus Clarithromycin

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00321178
• Other study ID #: BURULICODRUGTRIAL
• Secondary ID: EU FP6 2003-INCO
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: May 2, 2006
• Last updated: June 29, 2010
• Start date: May 2006
• Est. completion date: February 2009

Study information

• Verified date: April 2010
• Source: University Medical Center Groningen
• Contact: n/a
• Is FDA regulated: No
• Health authority: Ghana: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

The standard for treatment Buruli ulcer disease (BUD) used to be surgery but the WHO now advises streptomycin (S, 15 mg/kg daily, intramuscularly) and rifampicin (R,10 mg/kg daily) along with surgery. This preliminary advice was based on observations in 21 patients with pre-ulcerative lesions of BUD, who were given daily SR treatment for varying periods of time. In patients treated with SR for at least 4 weeks, M. ulcerans could no longer be cultured from excised lesions. SR has been introduced without a formal evaluation or comparison with other treatments have been conducted or published, but the impression is that this treatment is beneficial and may cure BUD without additional surgical management.

This study protocol evaluated the hypothesis that early, limited lesions of BUD(pre-ulcerative or ulcerated lesions, ≤ 10 cm maximum diameter), can be healed without recurrence using antimycobacterial drug therapy, without the need for debridement surgery.

In endemic regions in Ghana, patients will be actively recruited and followed if ≥ 5 years of age, and with early (i.e., onset < 6 months) BUD.

• consent by patients and / or care givers / legal representatives

• clinical evaluation, and by

• analysis of three 0.3 cm punch biopsies under local anaesthesia.

• disease confirmation: dry reagent-based polymerase chain reaction (DRB-PCR IS2404)

• randomization: either SR for 8 weeks, or 4 weeks of SR followed by R and clarithromycin (C)

• stratification: ulcerative or pre-ulcerative lesions.

Biopsies processed for histopathology, DRB-PCR-, microscopy, culture, genomic, and sensitivity tests. Lesions assessed regularly for progression or healing during treatment. Drug toxicity monitoring included blood cell counts, liver enzymes and renal tests; and ECG and audiographic tests.

Primary endpoint: healing without recurrence at 12 months follow-up after start of treatment Secondary endpoint: reduction in lesion surface area and/or clinically assessed improvement on completion of treatment, averting the need for debridement surgery.

Recurrences biopsied for confirmation, using PCR, histopathology, and culture. Sample size calculation: 2x74 fully evaluable patients; 80% power to detect a difference of 20 % in recurrence-free cure 12 months after start of treatment between the two groups (60 versus 80%). A Data Safety and Monitoring Board made interim analysis assessments.

Description:

Buruli ulcer disease (BUD) is caused by infection with Mycobacterium ulcerans. It usually starts as a small nodule under the skin but may progress to an ulcerative lesion; and eventually large, usually painless ulcers may develop. When it heals - with surgery or without - it may cause severe scarring resulting in disability and deformity. BUD has emerged as an important infectious disease among rural populations in West Africa. The standard treatment used to be surgical excision for all forms and stages. In 2004. The World Health Organisation advised the use of streptomycin (S, 15 mg/kg daily, intramuscularly) and rifampicin (R,10 mg/kg daily) along with surgery. This preliminary advice was based on the observation in 21 patients with pre-ulcerative lesions of BUD, who were given daily SR treatment for varying periods of time. If patients had received such treatment for at least 4 weeks, M. ulcerans could not be cultured again from the lesions that were excised. The treatment has been implemented in areas with poor access to surgical facilities, in Pobe, Benin, and although no formal evaluation or comparison with other treatments have been conducted or published, the impression is that this treatment is probably beneficial and may cure BUD without the need for additional surgical management.

This study protocol was designed to evaluate the hypothesis that early, limited lesions of Buruli ulcer (M. ulcerans disease; pre-ulcerative or ulcerated lesions, less than or equal to 10 maximum diameter), can be healed without recurrence using antimycobacterial drug therapy, without the need for debridement surgery.

In endemic regions in Ghana, active case finding will be followed by accrual of patients

• 5 years of age and over, with

• limited early (i.e., onset less than 6 months) lesions of Buruli ulcer.

After appropriate consent by patients and / or their care givers or legal representatives, patients will be diagnosed both by

• clinical evaluation, and

• by analysis of three punch biopsies (0.3 cm each) under local anaesthesia.

Only patients with confirmation of M. ulcerans disease - presence of dry reagent-based polymerase chain reaction (DRB-PCR) signal with insertion sequence IS2404, were to be randomised to receive either SR for 8 weeks, or 4 weeks of SR followed by oral treatment consisting of R and clarithromycin (C), as allocated by a computer-generated program; patients will be stratified for ulcerative or pre-ulcerative lesions.

Patients who meet the clinical criteria for M ulcerans disease but are PCR negative, will be offered 8 weeks RS treatment, as is presently provisionally recommended by WHO, and will be evaluated separately, according to the protocol for patients allocated to 8 weeks RS treatment. All biopsies from lesions will be subjected to histopathology, DRB-PCR-, microscopy, culture, genomic, sensitivity tests and external quality control in laboratories in Kumasi (KNUST), Hamburg (BNITM), Munich (DITM) and Antwerp (ITM). Lesions will be assessed regularly for progression or healing during treatment. Drug toxicity will likewise be monitored: renal and audiographic tests for S and C, ECG for C, and liver enzymes for R and C, and blood cell counts for C.

The primary endpoint is healing without recurrence at 12 months follow-up after start of treatment Secondary endpoint is reduction in lesion surface area and/or clinically assessed improvement on completion of treatment, averting the need for debridement surgery.

Recurrences will be biopsied for confirmation, using PCR, histopathology, and culture. In all, 200 patients will need to be screened according to protocol, and 2x74 evaluable patients will be randomised based on a power analysis to detect a difference of 20 % in recurrence-free cure 12 months after start of treatment between the two groups (60 versus 80%). A Data Safety and Monitoring Board will make interim analyses.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 151
• Est. completion date: February 2009
• Est. primary completion date: January 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 5 Years and older

Eligibility

Inclusion Criteria:

• Male or female patients

• At least 5 years of age

• A clinical diagnosis of early M. ulcerans disease including:

• Nodules

• Plaques and small ulcers with or without oedema and less than or equal to 10cm in maximum diameter

• Disease duration no longer than six months

• DRB-PCR positive for M. ulcerans

Exclusion Criteria:

• Treatment with macrolide or quinolone antibiotics, or antituberculous medication, or immunomodulatory drugs including corticosteroids within the previous one month.

• Current treatment with any drugs likely to interact with the study medication, e.g, anticoagulants, cyclosporin, phenytoin, oral contraceptive, and phenobarbitone.

• History of hypersensitivity to rifampicin, streptomycin and or clarithromycin.

• History or having current clinical signs of ascites, jaundice, partial or complete deafness, myasthenia gravis, renal dysfunction (known or suspected), diabetes mellitus, and immune compromise; or evidence for past or present tuberculosis.

• Pregnancy

• Inability to take oral medication or having gastrointestinal disease likely to interfere with drug absorption.

• Excessive alcohol intake.

• Any situation or condition which may compromise ability to comply with the trial procedures.

• Lack of willingness to give informed consent (and/or assent by parent/legal representative).

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Buruli Ulcer
• Mycobacterium Infections
• Mycobacterium Ulcerans

Intervention

Drug:
• SR4 - switch to CR4
switch to oral treatment after 4 weeks SR 'standard' therapy

Locations

Country	Name	City	State
Ghana	Agogo Hospital	Agogo	Ashanti Region
Ghana	Nkawie-Toaso Hospital	Nkawie	Ashanti Region

Sponsors (1)

Lead Sponsor	Collaborator
University Medical Center Groningen

Country where clinical trial is conducted

Ghana, 

References & Publications (3)

Etuaful S, Carbonnelle B, Grosset J, Lucas S, Horsfield C, Phillips R, Evans M, Ofori-Adjei D, Klustse E, Owusu-Boateng J, Amedofu GK, Awuah P, Ampadu E, Amofah G, Asiedu K, Wansbrough-Jones M. Efficacy of the combination rifampin-streptomycin in preventing growth of Mycobacterium ulcerans in early lesions of Buruli ulcer in humans. Antimicrob Agents Chemother. 2005 Aug;49(8):3182-6. — View Citation

van der Werf TS, Stienstra Y, Johnson RC, Phillips R, Adjei O, Fleischer B, Wansbrough-Jones MH, Johnson PD, Portaels F, van der Graaf WT, Asiedu K. Mycobacterium ulcerans disease. Bull World Health Organ. 2005 Oct;83(10):785-91. Epub 2005 Nov 10. Review. — View Citation

van der Werf TS, van der Graaf WT, Tappero JW, Asiedu K. Mycobacterium ulcerans infection. Lancet. 1999 Sep 18;354(9183):1013-8. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	healing without recurrence and without debridement surgery at 12 months follow-up after start of treatment		12 months follow-up after start of treatment	Yes
Secondary	reduction in lesion surface area and/or clinically assessed improvement on completion of treatment, averting the need for debridement surgery		during treatment and follow-up x 12 months	Yes
Secondary	adverse events		during treatment and follow-up x 12 months	Yes
Secondary	functional limitations		at end of follow-up (12 months)	Yes

External Links

•   Global Buruli ulcer Initiative, World Health organisation
•   University Medical Centre Groningen, University of Groningen, the Netherlands