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

• Status: Completed
• Trial end date: 2009-02-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2/Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University Medical Center Groningen
• Treatments: Clarithromycin; Rifampin; Streptomycin

Criteria

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).