BURULICO Drug Trial Study Protocol: RCT SR8/SR4+CR4, GHANA
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Buruli Ulcer Mycobacterium Ulcerans |
Drug: SR4 - switch to CR4 |
Phase 2 Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment |
| 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 |
- 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 ] [ Designated as safety issue: Yes ]
- 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 ] [ Designated as safety issue: Yes ]
- adverse events [ Time Frame: during treatment and follow-up x 12 months ] [ Designated as safety issue: Yes ]
- functional limitations [ Time Frame: at end of follow-up (12 months) ] [ Designated as safety issue: Yes ]
| Enrollment: | 151 |
| Study Start Date: | May 2006 |
| Study Completion Date: | February 2009 |
| Primary Completion Date: | January 2008 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
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 Name: 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 Name: clarithromycin: Clacid
|
Show Detailed Description Eligibility| Ages Eligible for Study: | 5 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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).
Contacts and Locations| Ghana | |
| Agogo Hospital | |
| Agogo, Ashanti Region, Ghana | |
| Nkawie-Toaso Hospital | |
| Nkawie, Ashanti Region, Ghana | |
| Principal Investigator: | Tjip S van der Werf, MD PhD | University Medical Centre Groningen, University of Groningen, the Netherlands |
More Information
Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Prof TS van der Werf, UMCG, University of Groningen, the Netherlands |
| ClinicalTrials.gov Identifier: | NCT00321178 History of Changes |
| Other Study ID Numbers: | BURULICODRUGTRIAL, EU FP6 2003-INCO-Dev2-015476 |
| Study First Received: | May 2, 2006 |
| Last Updated: | June 29, 2010 |
| Health Authority: | Ghana: Ministry of Health |
Keywords provided by University Medical Centre Groningen:
|
Mycobacterium ulcerans Buruli ulcer Ghana randomized comparison |
streptomycin rifampicin clarithromycin |
Additional relevant MeSH terms:
|
Mycobacterium Infections Ulcer Buruli Ulcer Actinomycetales Infections Gram-Positive Bacterial Infections Bacterial Infections Pathologic Processes Mycobacterium Infections, Atypical Skin Ulcer Skin Diseases Rifampin Streptomycin |
Clarithromycin Antibiotics, Antitubercular Anti-Bacterial Agents Anti-Infective Agents Therapeutic Uses Pharmacologic Actions Antitubercular Agents Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Leprostatic Agents Nucleic Acid Synthesis Inhibitors Protein Synthesis Inhibitors |
ClinicalTrials.gov processed this record on June 17, 2013