BURULICO Drug Trial Study Protocol: RCT SR8/SR4+CR4, GHANA - Full Text View

Sponsor:	University Medical Centre Groningen
Information provided by:	University Medical Centre Groningen
ClinicalTrials.gov Identifier:	NCT00321178

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 II Phase III

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

Resource links provided by NLM:

MedlinePlus related topics: Mycobacterial Infections

Drug Information available for: Streptomycin Rifampin Clarithromycin Streptomycin sulfate

U.S. FDA Resources

Further study details as provided by University Medical Centre Groningen:

Primary Outcome Measures:

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 ]

Secondary Outcome Measures:

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

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).

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00321178

Locations

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

Sponsors and Collaborators

University Medical Centre Groningen

Investigators

Principal Investigator:

Tjip S van der Werf, MD PhD

University Medical Centre Groningen, University of Groningen, the Netherlands

More Information

Additional Information:

Global Buruli ulcer Initiative, World Health organisation This link exits the ClinicalTrials.gov site

6th Frame Work, European Union This link exits the ClinicalTrials.gov site

BURULICO consortium home page This link exits the ClinicalTrials.gov site

Kumasi Centre for Collaborative Research, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana This link exits the ClinicalTrials.gov site

University Medical Centre Groningen, University of Groningen, the Netherlands This link exits the ClinicalTrials.gov site

Publications:

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.

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

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.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Nienhuis WA, Stienstra Y, Thompson WA, Awuah PC, Abass KM, Tuah W, Awua-Boateng NY, Ampadu EO, Siegmund V, Schouten JP, Adjei O, Bretzel G, van der Werf TS. Antimicrobial treatment for early, limited Mycobacterium ulcerans infection: a randomised controlled trial. Lancet. 2010 Feb 20;375(9715):664-72. Epub 2010 Feb 3.

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 February 09, 2012