WHO Drug Study for Buruli Ulcer - Comparison of SR8 and CR8

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2013 by University Medical Centre Groningen
Sponsor:
Collaborators:
University of Groningen
Faculté de Médecine P&M Curie, Paris-6 - Site Pitié-Salpêtrière, France
Drugs for Neglected Diseases initiative (DNDi) Africa, Nairobi, Kenya
World Alliance for Wound and Lymphoedema Care, Switzerland
Inserm U892/CNRS 699 & labo bactériologie, Université et CHU d'Angers- IRIS, Angers, France
Institute of Tropical Medicine, Antwerp, Belgium
National Buruli ulcer Control Programme, Ghana Health Service, Accra, Ghana
School of Medical Sciences, Kwame Nkrumah University of Science & Technology, Kumasi, Ghana
Komfo Anokye Teaching Hospital, Kumasi, Ghana
Kumasi Center for Collaborative Research into Tropical Medicine, Kumasi, Ghana
Korle-Bu Teaching Hospital, Accra, Ghana
School of Public Health, University of Ghana, Legon, Ghana
Noguchi Memorial Institute of Medical Research, Accra, Ghana
Ministry of Health, Benin
Information provided by (Responsible Party):
Tjip van der Werf, University Medical Centre Groningen
ClinicalTrials.gov Identifier:
NCT01659437
First received: August 2, 2012
Last updated: August 4, 2013
Last verified: August 2013
  Purpose

This is a WHO-sponsored trial.

Combination therapy with streptomycin and rifampicin has been the standard antibiotic treatment for M. ulcerans infection since 2004. In March 2010, a WHO Technical Advisory Group recommended that a trial be carried out to develop a fully oral treatment for the disease. Although the current treatment is effective, injection with streptomycin is a problem. Several small observational studies (published and unpublished) have shown that a fully oral treatment is promising.

This WHO sponsored study will be a randomized, controlled open label non-inferiority phase II/III, multi-centre trial (1 centre in Benin and 4 centres in Ghana), with two parallel treatment groups. The ultimate goal is to search for an effective alternative treatment to the current standard WHO-recommended therapy for all forms of Buruli ulcer, which includes injections of streptomycin with inherent logistic, operational and safety disadvantages.

Financial and material support:

  1. American Leprosy Missions, USA
  2. Raoul Follereau Foundation, France
  3. MAP International, USA
  4. Sanofi, France
  5. 7th Framework Programme of the European Union: BuruliVac project (241500)
  6. Aranz Medical Limited, New Zealand

Condition Intervention Phase
Mycobacterium Ulcerans Infection
Drug: Clarithromycin Extended Release
Drug: Streptomycin intramuscular injection
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Randomized Controlled Trial Comparing Efficacy of 8 Weeks Treatment With Clarithromycin and Rifampicin Versus Streptomycin and Rifampicin for Buruli Ulcer (M. Ulcerans Infection)

Resource links provided by NLM:


Further study details as provided by University Medical Centre Groningen:

Primary Outcome Measures:
  • healing without recurrence and without excision surgery [ Time Frame: 12 months after start of treatment ] [ Designated as safety issue: No ]
    complete epithelialisation and absence of swelling at the site of original infection, measured 12 months after start of treatment; lesion site will be examined by inspection and palpation, and documented by digital camera; digital images will be examined by panel of wound experts unaware of treatment allocation


Secondary Outcome Measures:
  • Recurrence rate within 12 months of treatment initiation [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    number of recurrent lesions occurring after initial healing within 12 months after start of treatment

  • Rate of treatment failure within 12 months of treatment initiation [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    proportion of treatment failure will be compared between groups

  • Rate of paradoxical response within 12 months of treatment initiation [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    paradoxical responses that have occurred during BUD treatment will be compared in both treatment arms

  • Proportion of patients with reduction in lesion surface area within 12 months of treatment initiation [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    if not cured, will there be a difference between groups in terms of reduction of lesion size?

  • Time taken for complete lesion healing within 12 months of treatment initiation [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    do lesions heal faster in one of the two treatments?

  • Proportion (%) of patients with complete healing without additional surgery or relapse [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Interval between healing and recurrence [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    if recurrences occur, there might be a difference in time between healing and recurrences between treatment groups

  • Proportion of each type of surgery within 12 months of treatment initiation [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    We do not expect surgery but IF doctors operate, which type of surgery would doctors use, and does this differ between groups?

  • Time from treatment initiation to surgery if any [ Time Frame: 12months ] [ Designated as safety issue: No ]
    does the timing of surgery differ between groups for the proportion of patients in whom doctors decide to operate?

  • Proportion of patients with residual functional limitations [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    do treatments differ in terms of chance to develop functional limitations?

  • Treatment discontinuation and compliance rates [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
    one treatment might be better tolerated than the other; do treatments differ in terms of adherence problems, and do participants in any of these two treatment arms differ in terms of the chance to discontinue the treatment?

  • Incidence of all adverse effects (AEs) within 12 months of treatment initiation [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    adverse effects occurring during or after treatment may be different between treatments


Estimated Enrollment: 415
Study Start Date: December 2012
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: SR8
Streptomycin (S: 15 mg/kg per day, intramuscularly) in combination with rifampicin (R: 10 mg/kg per day, orally) for 8 weeks
Drug: Streptomycin intramuscular injection
daily intramuscular drug injection
Experimental: CR8
Clarithromycin (C: 150 mg/kg per day, oral extended release formulation) in combination with rifampicin (10 mg/kg per day, orally) for 8 weeks
Drug: Clarithromycin Extended Release
oral administration of Clarithromycin extended release

Detailed Description:

A total of 415 patients in whom Buruli ulcer has been clinically diagnosed will be included in the study, which will consist of 332 cases of category I and II Buruli ulcers (<10 cm) confirmed by polymerase chain reaction (PCR), plus 83 non PCR-confirmed Buruli ulcers. Patients will be randomized to receive treatment with the two antibiotic regimens as follows:

(i) Regimen I (SR8): 15 mg/kg streptomycin per day intramuscular injection for 8 weeks plus 10 mg/kg per day oral rifampicin for 8 weeks; (ii) Regimen II (CR8): 15 mg/kg per day oral extended-release clarithromycin for 8 weeks plus 10 mg/kg per day oral rifampicin for 8 weeks.

Assessments before, during and after the course of antibiotic treatment will include full medical history, clinical assessments and monitoring of vital signs, assessment of the lesion, laboratory investigations, hearing test, electrocardiogram, pregnancy test, voluntary HIV counseling and testing, and functional limitation assessment. The primary efficacy parameters are healing without recurrence and without excision surgery 12 months after the start of treatment.

The primary endpoint will be assessed by a panel of experts unaware of the treatment ('single blinded' for treatment allocation).

Statistician:

Mr Bruno Scherrer, Consultant, Drugs for Neglected Diseases initiative, Switzerland

Data Management:

Mr Raymond Omollo, Drugs for Neglected Diseases initiative (DNDi) Africa

  Eligibility

Ages Eligible for Study:   5 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • All patients (both genders) with a clinical diagnosis of BUD (categories: I and II, cross-sectional diameter ≤ 10cm) as agreed by study site treatment team led by the lead clinicians

Exclusion criteria:

  1. Patients with lesion sizes >10cm in cross-sectional diameter
  2. Children < 5 years, or < 20 kilograms body weight
  3. Pregnancy (self-reported, clinically diagnosed, or urine test (beta-hCG) positive
  4. Patients with previous treatment of Buruli ulcer, tuberculosis or leprosy with at least one of the study drugs (rifampicin, streptomycin, clarithromycin)
  5. Patients with history of hypersensitivity to rifampicin and/or streptomycin and/or clarithromycin
  6. Patients with previous treatment with macrolide or quinolone antibiotics, or antituberculosis medication, or immuno-modulatory drugs including corticosteroids within one month
  7. Patients with current treatment with any drugs likely to interact with the study medication, e.g, anticoagulants, cyclosporin, phenytoin, and phenobarbitone. Users of oral contraceptives should be notified that such contraceptive is less reliable if taken with rifampicin; alternative (mechanical) contraceptive methods will be discussed with the study participant
  8. Patients with co-infection with HIV
  9. Patients with history or having current clinical signs of ascites, jaundice, partial or complete deafness, myasthenia gravis, renal dysfunction (known or suspected), diabetes mellitus, and severe immune compromise (e.g., immunosuppressive drugs after organ transplant), or evidence of (previous) tuberculosis, Buruli ulcer or leprosy; or terminal illness (e.g., metastasized cancer)
  10. Patients who are unable to take oral medication or having gastrointestinal disease likely to interfere with drug absorption
  11. Patients with known or suspected bowel strictures who cannot tolerate macrolide antibiotics such as clarithromycin
  12. Patients with mental condition, including addiction with substance abuse (alcohol, qat, etc) likely to interfere with possibility to comply with the study protocol
  13. Patients who are not willing to give informed pre-consent, and consent (patient and/or parent/legal representative), or withdrawal of consent
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01659437

Contacts
Contact: Tjip S van der Werf, MD, PhD 0031623833846 / 0031503611501 t.s.van.der.werf@umcg.nl
Contact: Kingsley Asiedu, MD, MPH 0041227912803 asieduk@who.int

Locations
Benin
Pobè Treatment Center Recruiting
Pobè, Benin
Contact: Annick Chauty, MD       achauty@gmail.com   
Contact: Marie Françoise Ardent         
Sub-Investigator: Annick Chauty, MD         
Ghana
Agogo Presbyterian Hospital Recruiting
Agogo, Ghana
Contact: William Thompson, MD       thomasmnsh@yahoo.com   
Contact: Kabiru M Abass    00233244533129    abass@agogopresbyhospital.org   
Sub-Investigator: William Thompson, MD         
Dunkwa Government Hospital Recruiting
Dunkwa, Ghana
Contact: Godfred Sarpong, MD       kobbymed@yahoo.com   
Contact: Kojo Lindsey, MD         
Sub-Investigator: Godfred Sarpong, MD         
Nkawie-Toase Government Hospital Recruiting
Nkawie, Ghana
Contact: Peter Awuah, MD       pcawuah@yahoo.com   
Contact: Wilson Tuah       tuah_wilson@yahoo.com   
Sub-Investigator: Peter Awuah, MD         
Tepa Government Hosital Recruiting
Tepa, Ghana
Contact: Mark Forson, MD         
Contact: Nana A Bobi         
Sub-Investigator: Mark Forson, MD         
Sponsors and Collaborators
University Medical Centre Groningen
University of Groningen
Faculté de Médecine P&M Curie, Paris-6 - Site Pitié-Salpêtrière, France
Drugs for Neglected Diseases initiative (DNDi) Africa, Nairobi, Kenya
World Alliance for Wound and Lymphoedema Care, Switzerland
Inserm U892/CNRS 699 & labo bactériologie, Université et CHU d'Angers- IRIS, Angers, France
Institute of Tropical Medicine, Antwerp, Belgium
National Buruli ulcer Control Programme, Ghana Health Service, Accra, Ghana
School of Medical Sciences, Kwame Nkrumah University of Science & Technology, Kumasi, Ghana
Komfo Anokye Teaching Hospital, Kumasi, Ghana
Kumasi Center for Collaborative Research into Tropical Medicine, Kumasi, Ghana
Korle-Bu Teaching Hospital, Accra, Ghana
School of Public Health, University of Ghana, Legon, Ghana
Noguchi Memorial Institute of Medical Research, Accra, Ghana
Ministry of Health, Benin
Investigators
Principal Investigator: Tjip S van der Werf, MD, PhD University of Groningen, University Medical Centre Groningen
Study Director: Richard O Phillips, MD, PhD Komfo Anokye Teaching Hospital, Kwame Nkrumah University of Science & Technology, Kumasi, Ghana
Study Director: Annick Chauty, MD Pobè Health Centre, Pobè, Bénin
Study Chair: Kingsley B Asiedu, MD, MPH WHO, GBUI, Geneva, Switserland
  More Information

Additional Information:
Publications:
Responsible Party: Tjip van der Werf, Professor, University Medical Centre Groningen
ClinicalTrials.gov Identifier: NCT01659437     History of Changes
Other Study ID Numbers: T9-370-1
Study First Received: August 2, 2012
Last Updated: August 4, 2013
Health Authority: Ghana : Food and Drugs Board
Ghana: Committee on Human Research
Benin: Comité National Provisoire d'Ethique pour la Recherche en Santé

Keywords provided by University Medical Centre Groningen:
M. ulcerans
Buruli ulcer
drug trial
clarithromycin

Additional relevant MeSH terms:
Mycobacterium Infections
Mycobacterium Infections, Nontuberculous
Infection
Communicable Diseases
Buruli Ulcer
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Skin Ulcer
Skin Diseases
Clarithromycin
Streptomycin
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on October 02, 2014