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

NCT00321178 | Completed Phase 2 DMC

• 2 other identifiers: BURULICODRUGTRIALEU FP6 2003-INCO-Dev2-015476
• Study Type: interventional
• Target: 151
• Locations: 1 country
• Sites: 2

Brief 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.

Conditions

Buruli Ulcer; Mycobacterium Ulcerans

Keywords

Mycobacterium ulcerans; Buruli ulcer; Ghana; randomized comparison; streptomycin; rifampicin; clarithromycin

Outcome Measures

Primary Outcomes (1)

• healing without recurrence and without debridement surgery at 12 months follow-up after start of treatment

  12 months follow-up after start of treatment

Secondary Outcomes (3)

• reduction in lesion surface area and/or clinically assessed improvement on completion of treatment, averting the need for debridement surgery

  during treatment and follow-up x 12 months

• adverse events

  during treatment and follow-up x 12 months

• functional limitations

  at end of follow-up (12 months)

Study Arms (2)

SR4/CR4

EXPERIMENTAL

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

SR8

ACTIVE COMPARATOR

standard treatment consisting of 8 weeks of streptomycin and rifampicin

Drug: SR4 - switch to CR4

Interventions

SR4 - switch to CR4 DRUG

switch to oral treatment after 4 weeks SR 'standard' therapy

Also known as: clarithromycin: Clacid

SR4/CR4; SR8

Eligibility Criteria

• Age: 5 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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).

Sponsors & Collaborators

• University Medical Center Groningen: lead

Study Sites (2)

Agogo Hospital

Agogo, Ashanti Region, Ghana

Location

Nkawie-Toaso Hospital

Nkawie, Ashanti Region, Ghana

Location

Related Publications (6)

• 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.

  PMID: 16283056 BACKGROUND

• van der Werf TS, van der Graaf WT, Tappero JW, Asiedu K. Mycobacterium ulcerans infection. Lancet. 1999 Sep 18;354(9183):1013-8. doi: 10.1016/S0140-6736(99)01156-3.

  PMID: 10501380 BACKGROUND

• 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. doi: 10.1128/AAC.49.8.3182-3186.2005.

  PMID: 16048922 BACKGROUND

• Barogui YT, Klis SA, Johnson RC, Phillips RO, van der Veer E, van Diemen C, van der Werf TS, Stienstra Y. Genetic Susceptibility and Predictors of Paradoxical Reactions in Buruli Ulcer. PLoS Negl Trop Dis. 2016 Apr 20;10(4):e0004594. doi: 10.1371/journal.pntd.0004594. eCollection 2016 Apr.

  PMID: 27097163 DERIVED

• Nienhuis WA, Stienstra Y, Abass KM, Tuah W, Thompson WA, Awuah PC, Awuah-Boateng NY, Adjei O, Bretzel G, Schouten JP, van der Werf TS. Paradoxical responses after start of antimicrobial treatment in Mycobacterium ulcerans infection. Clin Infect Dis. 2012 Feb 15;54(4):519-26. doi: 10.1093/cid/cir856. Epub 2011 Dec 7.

  PMID: 22156855 DERIVED

• 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. doi: 10.1016/S0140-6736(09)61962-0. Epub 2010 Feb 3.

  PMID: 20137805 DERIVED

Related Links

• Global Buruli ulcer Initiative, World Health organisation
• Kumasi Centre for Collaborative Research, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
• University Medical Centre Groningen, University of Groningen, the Netherlands

MeSH Terms

Conditions

Buruli Ulcer

Condition Hierarchy (Ancestors)

Mycobacterium Infections, Nontuberculous; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Skin Ulcer; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Tjip S van der Werf, MD PhD

  University Medical Centre Groningen, University of Groningen, the Netherlands

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: May 2, 2006
• First Posted: May 3, 2006
• Study Start: May 1, 2006
• Primary Completion: January 1, 2008
• Study Completion: February 1, 2009
• Last Updated: June 30, 2010

Record last verified: 2010-04

Locations

GH (2)