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

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ClinicalTrials.gov Identifier: NCT01659437
Recruitment Status : Completed
First Posted : August 7, 2012
Last Update Posted : September 26, 2019
Sponsor:
Collaborators:
University of Groningen
Faculté de Médecine P&M Curie, Paris-6 - Site Pitié-Salpêtrière, France
Drugs for Neglected Diseases
World Alliance for Wound and Lymphoedema Care, Switzerland
Inserm U892/CNRS 699 bactériologie, Université CHU;Angers- IRIS France
Institute of Tropical Medicine, Antwerp, Belgium
National Buruli ulcer Control Programme, Ghana Health Service, Accra, Ghana
School of Med Sciences, Kwame Nkrumah Univ of Sci & Techn, Kumasi, Ghana
Komfo Anokye Teaching Hospital
Kumasi Center for Collaborative Research into Tropical Medicine, Kumasi, Ghana
Plastic Surgery and Burns Centre, Korle-Bu Teaching Hospital, Accra, Ghana
University of Ghana
Noguchi Memorial Institute of Medical Research, Accra, Ghana
Program Nat de Lutte contre la Lèpre et l'UB;Ulcère de Buruli, Cotonou, Benin
Information provided by (Responsible Party):
Tjip van der Werf, University Medical Center Groningen

Tracking Information
First Submitted Date  ICMJE August 2, 2012
First Posted Date  ICMJE August 7, 2012
Last Update Posted Date September 26, 2019
Study Start Date  ICMJE December 2012
Actual Primary Completion Date December 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 6, 2012)
healing without recurrence and without excision surgery [ Time Frame: 12 months after start of treatment ]
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
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01659437 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 6, 2012)
  • Recurrence rate within 12 months of treatment initiation [ Time Frame: 12 months ]
    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 ]
    proportion of treatment failure will be compared between groups
  • Rate of paradoxical response within 12 months of treatment initiation [ Time Frame: 12 months ]
    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 ]
    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 ]
    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 ]
  • Interval between healing and recurrence [ Time Frame: 12 months ]
    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 ]
    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 ]
    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 ]
    do treatments differ in terms of chance to develop functional limitations?
  • Treatment discontinuation and compliance rates [ Time Frame: 8 weeks ]
    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 ]
    adverse effects occurring during or after treatment may be different between treatments
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE WHO Drug Study for Buruli Ulcer - Comparison of SR8 and CR8
Official Title  ICMJE Randomized Controlled Trial Comparing Efficacy of 8 Weeks Treatment With Clarithromycin and Rifampicin Versus Streptomycin and Rifampicin for Buruli Ulcer (M. Ulcerans Infection)
Brief Summary

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
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

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Mycobacterium Ulcerans Infection
Intervention  ICMJE
  • Drug: Clarithromycin Extended Release
    oral administration of Clarithromycin extended release
  • Drug: Streptomycin intramuscular injection
    daily intramuscular drug injection
Study Arms  ICMJE
  • 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
    Intervention: Drug: Streptomycin intramuscular injection
  • Experimental: CR8
    Clarithromycin (C: 15 mg/kg per day, oral extended release formulation) in combination with rifampicin (10 mg/kg per day, orally) for 8 weeks
    Intervention: Drug: Clarithromycin Extended Release
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 24, 2019)
310
Original Estimated Enrollment  ICMJE
 (submitted: August 6, 2012)
415
Actual Study Completion Date  ICMJE January 2018
Actual Primary Completion Date December 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 5 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Benin,   Ghana
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01659437
Other Study ID Numbers  ICMJE T9-370-1
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: after publication, IPD will be made available at the time of publication; enrollment is complewted with 310 participants enrolled by Dec 2017; final report submitted for publication Sept 2019
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Time Frame: data analysis report as well as data in OpenClinica deposited with DNDi Regional Africa Office Nairobi
Responsible Party Tjip van der Werf, University Medical Center Groningen
Study Sponsor  ICMJE University Medical Center Groningen
Collaborators  ICMJE
  • University of Groningen
  • Faculté de Médecine P&M Curie, Paris-6 - Site Pitié-Salpêtrière, France
  • Drugs for Neglected Diseases
  • World Alliance for Wound and Lymphoedema Care, Switzerland
  • Inserm U892/CNRS 699 bactériologie, Université CHU;Angers- IRIS France
  • Institute of Tropical Medicine, Antwerp, Belgium
  • National Buruli ulcer Control Programme, Ghana Health Service, Accra, Ghana
  • School of Med Sciences, Kwame Nkrumah Univ of Sci & Techn, Kumasi, Ghana
  • Komfo Anokye Teaching Hospital
  • Kumasi Center for Collaborative Research into Tropical Medicine, Kumasi, Ghana
  • Plastic Surgery and Burns Centre, Korle-Bu Teaching Hospital, Accra, Ghana
  • University of Ghana
  • Noguchi Memorial Institute of Medical Research, Accra, Ghana
  • Program Nat de Lutte contre la Lèpre et l'UB;Ulcère de Buruli, Cotonou, Benin
Investigators  ICMJE
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
PRS Account University Medical Center Groningen
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP