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

June 29, 2010 updated by: University Medical Center Groningen

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Interventional

Enrollment (Actual)

151

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Ghana
    • Ashanti Region
      • Agogo, Ashanti Region, Ghana
        • Agogo Hospital
      • Nkawie, Ashanti Region, Ghana
        • Nkawie-Toaso Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

5 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: SR4/CR4
after 4 weeks of standard treatment with streptomycin and rifampicin, patients in the experimental arm switch to oral treatment consisting of rifampicin and clarithromycin
Drug: SR4 - switch to CR4
switch to oral treatment after 4 weeks SR 'standard' therapy
Other Names:
  • clarithromycin: Clacid
Active Comparator: SR8
standard treatment consisting of 8 weeks of streptomycin and rifampicin
Drug: SR4 - switch to CR4
switch to oral treatment after 4 weeks SR 'standard' therapy
Other Names:
  • clarithromycin: Clacid

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
healing without recurrence and without debridement surgery at 12 months follow-up after start of treatment
Time Frame: 12 months follow-up after start of treatment
12 months follow-up after start of treatment

Secondary Outcome Measures

Outcome Measure
Time Frame
reduction in lesion surface area and/or clinically assessed improvement on completion of treatment, averting the need for debridement surgery
Time Frame: during treatment and follow-up x 12 months
during treatment and follow-up x 12 months
adverse events
Time Frame: during treatment and follow-up x 12 months
during treatment and follow-up x 12 months
functional limitations
Time Frame: at end of follow-up (12 months)
at end of follow-up (12 months)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Medical Center Groningen

Investigators

  • Principal Investigator: Tjip S van der Werf, MD PhD, University Medical Centre Groningen, University of Groningen, the Netherlands

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2006

Primary Completion (Actual)

January 1, 2008

Study Completion (Actual)

February 1, 2009

Study Registration Dates

First Submitted

May 2, 2006

First Submitted That Met QC Criteria

May 2, 2006

First Posted (Estimate)

May 3, 2006

Study Record Updates

Last Update Posted (Estimate)

June 30, 2010

Last Update Submitted That Met QC Criteria

June 29, 2010

Last Verified

April 1, 2010

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • BURULICODRUGTRIAL
  • EU FP6 2003-INCO-Dev2-015476

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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