Clinical Trial: Pathogenesis and Management of M. Ulcerans Disease, Buruli Ulcer

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Observational

Official Title: A Study of the Pathogenesis and Management of M. Ulcerans Disease, Buruli Ulcer

Brief Summary:

Buruli ulcer is a neglected tropical disease caused by infection with Mycobacterium ulcerans (Mu) in rural parts of West Africa. It causes large skin ulcers mainly in children aged 5 to 15 years. Access to treatment is limited and many cases present late. There have been major advances in understanding the mechanism of disease together with improved diagnosis and management. The aim of the proposed studies is to identify markers predictive of a rapid response to antibiotic treatment and to investigate the pathogenesis of paradoxical reactions and oedematous lesions in Mu disease.

Infection with Mu results in a nodule under the skin which enlarges and breaks down to form an ulcer. This is because Mu produces a toxin that spreads outwards and damages subcutaneous tissue. In recent years it has been found that antibiotic treatment for 8 weeks with daily tablets and intramuscular injections heals ulcers. This is unpleasant and it would be better if the treatment could be shortened. Our previous studies suggest this may be possible. Therefore a wide range of tests will be investigated in order to identify markers for people in whom the infection is at an early stage with low numbers of Mu bacteria and low levels of toxin in the skin. During antibiotic treatment the rate of healing will be measured to find out which markers are the most reliable.

In some patients new areas of inflammation develop despite treatment and this is called a paradoxical reaction. The immune response to Mu will be investigated serially during antibiotic treatment to investigate the cause of paradoxical reactions.

About 15% of patients have oedematous disease, the most severe form of Buruli ulcer. We will study the amount of Mu toxin produced by the strain of Mu cultured from patients with this form of th

Detailed Summary:

Procedures

Infected Participants

After collection of demographic data using standard World Health Organisation forms (BU01) together with a careful history to establish when early lesions (nodules, plaques and ulcers) were first observed, the type and dimensions of lesions will be documented together with digital photographs and tracings onto acetate sheets. For oedematous lesions only digital photographs will be obtained. Patients will be reviewed at 2 weekly intervals during standard antibiotic treatment (rifampicin 10mg/kg and streptomycin 15mg/kg) with further recordings of clinical data as is done for all routine patients. These measurements will enable calculation of rate of healing and healing time in relation to lesion size and type. Patients will be monitored for paradoxical reactions that occur after the start of treatment in about 8% of patients. These procedures are routinely provided as part of routine care of Buruli ulcer patients.

Samples

The additional samples required from patients for the study are an extra volume of blood (7ml) and 3 swabs taken on occasions (at baseline, week 4, 8, 12 and 16) only when the patient has a lesion at these time points. Swabs/fine needle aspirates are required to determine if organisms detected by polymerase chain reaction (PCR) are still viable, one for M. ulcerans culture, one for measurement of mycolactone concentration, and one for combined 16S ribosomal ribonucleic acid (rRNA) reverse transcriptase / insertion sequence IS2404 Real-Time qPCR assay (1).

For patients that develop paradoxical lesions during therapy an additional blood sample and 3 swabs/fine needle aspirates will be obtained at the time of the reaction for via
Sponsor: Kwame Nkrumah University of Science and Technology

Current Primary Outcome: Measurement of serum/plasma proteins in diseased and healthy subjects [ Time Frame: Assessed for diseased participants at baseline, 8, 12, 16 weeks and only at baseline for healthy subjects ]

Original Primary Outcome: Identification of a viability and serum biomarker [ Time Frame: 24 months ]

Current Secondary Outcome: Viable M. ulcerans and bacterial load measurement in tissue of diseased subjects [ Time Frame: Assessed at baseline, 4, 8, 12, 16 only if lesions are not healed ]

Original Secondary Outcome: identification of biomarkers of paradoxical reaction [ Time Frame: 24 months ]

Information By: Kwame Nkrumah University of Science and Technology

Dates:
Date Received: May 28, 2014
Date Started: May 2013
Date Completion: January 2018
Last Updated: March 22, 2017
Last Verified: March 2017