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

Primary Purpose

Mycobacterium Ulcerans Infection

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Clarithromycin Extended Release

Streptomycin intramuscular injection

About this trial

This is an interventional treatment trial for Mycobacterium Ulcerans Infection focused on measuring M. ulcerans, Buruli ulcer, drug trial, clarithromycin

Eligibility Criteria

5 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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:

Patients with lesion sizes >10cm in cross-sectional diameter
Children < 5 years, or < 20 kilograms body weight
Pregnancy (self-reported, clinically diagnosed, or urine test (beta-hCG) positive
Patients with previous treatment of Buruli ulcer, tuberculosis or leprosy with at least one of the study drugs (rifampicin, streptomycin, clarithromycin)
Patients with history of hypersensitivity to rifampicin and/or streptomycin and/or clarithromycin
Patients with previous treatment with macrolide or quinolone antibiotics, or antituberculosis medication, or immuno-modulatory drugs including corticosteroids within one month
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
Patients with co-infection with HIV
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)
Patients who are unable to take oral medication or having gastrointestinal disease likely to interfere with drug absorption
Patients with known or suspected bowel strictures who cannot tolerate macrolide antibiotics such as clarithromycin
Patients with mental condition, including addiction with substance abuse (alcohol, qat, etc) likely to interfere with possibility to comply with the study protocol
Patients who are not willing to give informed pre-consent, and consent (patient and/or parent/legal representative), or withdrawal of consent

Sites / Locations

Pobè Treatment Center
Agogo Presbyterian Hospital
Dunkwa Government Hospital
Nkawie-Toase Government Hospital
Tepa Government Hosital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

SR8

CR8

Arm Description

Streptomycin (S: 15 mg/kg per day, intramuscularly) in combination with rifampicin (R: 10 mg/kg per day, orally) for 8 weeks

Clarithromycin (C: 15 mg/kg per day, oral extended release formulation) in combination with rifampicin (10 mg/kg per day, orally) for 8 weeks

Outcomes

Primary Outcome Measures

healing without recurrence and without excision surgery

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

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

proportion of treatment failure will be compared between groups

Rate of paradoxical response within 12 months of treatment initiation

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

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

do lesions heal faster in one of the two treatments?

Proportion (%) of patients with complete healing without additional surgery or relapse

Interval between healing and recurrence

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

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

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

do treatments differ in terms of chance to develop functional limitations?

Treatment discontinuation and compliance rates

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

adverse effects occurring during or after treatment may be different between treatments

Full Information

NCT ID

NCT01659437

First Posted

August 2, 2012

Last Updated

September 24, 2019

Sponsor

University Medical Center Groningen

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

1. Study Identification

Unique Protocol Identification Number

NCT01659437

Brief Title

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

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)

Study Type

Interventional

2. Study Status

Record Verification Date

September 2019

Overall Recruitment Status

Completed

Study Start Date

December 2012 (undefined)

Primary Completion Date

December 2017 (Actual)

Study Completion Date

January 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University Medical Center Groningen

Collaborators

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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: American Leprosy Missions, USA Raoul Follereau Foundation, France MAP International, USA Sanofi, France 7th Framework Programme of the European Union: BuruliVac project (241500) 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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Mycobacterium Ulcerans Infection

Keywords

M. ulcerans, Buruli ulcer, drug trial, clarithromycin

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2, Phase 3

Interventional Study Model

Parallel Assignment

Masking

Outcomes Assessor

Allocation

Randomized

Enrollment

310 (Actual)

8. Arms, Groups, and Interventions

Arm Title

SR8

Arm Type

Active Comparator

Arm Description

Streptomycin (S: 15 mg/kg per day, intramuscularly) in combination with rifampicin (R: 10 mg/kg per day, orally) for 8 weeks

Arm Title

CR8

Arm Type

Experimental

Arm Description

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 Type

Drug

Intervention Name(s)

Clarithromycin Extended Release

Intervention Description

oral administration of Clarithromycin extended release

Intervention Type

Drug

Intervention Name(s)

Streptomycin intramuscular injection

Intervention Description

daily intramuscular drug injection

Primary Outcome Measure Information:

Title

healing without recurrence and without excision surgery

Description

Time Frame

12 months after start of treatment

Secondary Outcome Measure Information:

Title

Recurrence rate within 12 months of treatment initiation

Description

number of recurrent lesions occurring after initial healing within 12 months after start of treatment

Time Frame

12 months

Title

Rate of treatment failure within 12 months of treatment initiation

Description

proportion of treatment failure will be compared between groups

Time Frame

12 months

Title

Rate of paradoxical response within 12 months of treatment initiation

Description

paradoxical responses that have occurred during BUD treatment will be compared in both treatment arms

Time Frame

12 months

Title

Proportion of patients with reduction in lesion surface area within 12 months of treatment initiation

Description

if not cured, will there be a difference between groups in terms of reduction of lesion size?

Time Frame

12 months

Title

Time taken for complete lesion healing within 12 months of treatment initiation

Description

do lesions heal faster in one of the two treatments?

Time Frame

12 months

Title

Proportion (%) of patients with complete healing without additional surgery or relapse

Time Frame

12 months

Title

Interval between healing and recurrence

Description

if recurrences occur, there might be a difference in time between healing and recurrences between treatment groups

Time Frame

12 months

Title

Proportion of each type of surgery within 12 months of treatment initiation

Description

We do not expect surgery but IF doctors operate, which type of surgery would doctors use, and does this differ between groups?

Time Frame

12 months

Title

Time from treatment initiation to surgery if any

Description

does the timing of surgery differ between groups for the proportion of patients in whom doctors decide to operate?

Time Frame

12months

Title

Proportion of patients with residual functional limitations

Description

do treatments differ in terms of chance to develop functional limitations?

Time Frame

12 months

Title

Treatment discontinuation and compliance rates

Description

Time Frame

8 weeks

Title

Incidence of all adverse effects (AEs) within 12 months of treatment initiation

Description

adverse effects occurring during or after treatment may be different between treatments

Time Frame

12 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

5 Years

Accepts Healthy Volunteers

Eligibility 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: Patients with lesion sizes >10cm in cross-sectional diameter Children < 5 years, or < 20 kilograms body weight Pregnancy (self-reported, clinically diagnosed, or urine test (beta-hCG) positive Patients with previous treatment of Buruli ulcer, tuberculosis or leprosy with at least one of the study drugs (rifampicin, streptomycin, clarithromycin) Patients with history of hypersensitivity to rifampicin and/or streptomycin and/or clarithromycin Patients with previous treatment with macrolide or quinolone antibiotics, or antituberculosis medication, or immuno-modulatory drugs including corticosteroids within one month 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 Patients with co-infection with HIV 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) Patients who are unable to take oral medication or having gastrointestinal disease likely to interfere with drug absorption Patients with known or suspected bowel strictures who cannot tolerate macrolide antibiotics such as clarithromycin Patients with mental condition, including addiction with substance abuse (alcohol, qat, etc) likely to interfere with possibility to comply with the study protocol Patients who are not willing to give informed pre-consent, and consent (patient and/or parent/legal representative), or withdrawal of consent

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Tjip S van der Werf, MD, PhD

Organizational Affiliation

University of Groningen, University Medical Centre Groningen

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Richard O Phillips, MD, PhD

Organizational Affiliation

Komfo Anokye Teaching Hospital, Kwame Nkrumah University of Science & Technology, Kumasi, Ghana

Official's Role

Study Director

First Name & Middle Initial & Last Name & Degree

Annick Chauty, MD

Organizational Affiliation

Pobè Health Centre, Pobè, Bénin

Official's Role

Study Director

First Name & Middle Initial & Last Name & Degree

Kingsley B Asiedu, MD, MPH

Organizational Affiliation

WHO, GBUI, Geneva, Switserland

Official's Role

Study Chair

Facility Information:

Facility Name

Pobè Treatment Center

City

Pobè

Country

Benin

Facility Name

Agogo Presbyterian Hospital

City

Agogo

Country

Ghana

Facility Name

Dunkwa Government Hospital

City

Dunkwa

Country

Ghana

Facility Name

Nkawie-Toase Government Hospital

City

Nkawie Panyin

Country

Ghana

Facility Name

Tepa Government Hosital

City

Tepa

Country

Ghana

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing 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

IPD Sharing Time Frame

data analysis report as well as data in OpenClinica deposited with DNDi Regional Africa Office Nairobi

Citations:

PubMed Identifier

20137805

Citation

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.

Results Reference

background

PubMed Identifier

21148526

Citation

Chauty A, Ardant MF, Marsollier L, Pluschke G, Landier J, Adeye A, Goundote A, Cottin J, Ladikpo T, Ruf T, Ji B. Oral treatment for Mycobacterium ulcerans infection: results from a pilot study in Benin. Clin Infect Dis. 2011 Jan 1;52(1):94-6. doi: 10.1093/cid/ciq072.

Results Reference

background

PubMed Identifier

21152060

Citation

Gordon CL, Buntine JA, Hayman JA, Lavender CJ, Fyfe JA, Hosking P, Starr M, Johnson PD. All-oral antibiotic treatment for buruli ulcer: a report of four patients. PLoS Negl Trop Dis. 2010 Nov 30;4(11):e770. doi: 10.1371/journal.pntd.0000770. No abstract available.

Results Reference

background

PubMed Identifier

22272368

Citation

O'Brien DP, McDonald A, Callan P, Robson M, Friedman ND, Hughes A, Holten I, Walton A, Athan E. Successful outcomes with oral fluoroquinolones combined with rifampicin in the treatment of Mycobacterium ulcerans: an observational cohort study. PLoS Negl Trop Dis. 2012 Jan;6(1):e1473. doi: 10.1371/journal.pntd.0001473. Epub 2012 Jan 17.

Results Reference

background

PubMed Identifier

32171422

Citation

Phillips RO, Robert J, Abass KM, Thompson W, Sarfo FS, Wilson T, Sarpong G, Gateau T, Chauty A, Omollo R, Ochieng Otieno M, Egondi TW, Ampadu EO, Agossadou D, Marion E, Ganlonon L, Wansbrough-Jones M, Grosset J, Macdonald JM, Treadwell T, Saunderson P, Paintsil A, Lehman L, Frimpong M, Sarpong NF, Saizonou R, Tiendrebeogo A, Ohene SA, Stienstra Y, Asiedu KB, van der Werf TS; study team. Rifampicin and clarithromycin (extended release) versus rifampicin and streptomycin for limited Buruli ulcer lesions: a randomised, open-label, non-inferiority phase 3 trial. Lancet. 2020 Apr 18;395(10232):1259-1267. doi: 10.1016/S0140-6736(20)30047-7. Epub 2020 Mar 12.

Results Reference

derived

PubMed Identifier

30102705

Citation

Converse PJ, Almeida DV, Tasneen R, Saini V, Tyagi S, Ammerman NC, Li SY, Anders NM, Rudek MA, Grosset JH, Nuermberger EL. Shorter-course treatment for Mycobacterium ulcerans disease with high-dose rifamycins and clofazimine in a mouse model of Buruli ulcer. PLoS Negl Trop Dis. 2018 Aug 13;12(8):e0006728. doi: 10.1371/journal.pntd.0006728. eCollection 2018 Aug.

Results Reference

derived

Links:

URL

http://www.who.int/buruli/en/

Description

WHO Buruli ulcer website

Learn more about this trial

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

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