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Mycobacterium Ulcerans InfectionPhase 2/3NCT01659437

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

A Phase 2/3 study testing Clarithromycin Extended Release and Streptomycin intramuscular injection in people with Mycobacterium Ulcerans Infection, run by University Medical Center Groningen at 5 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 5 years and older
Conditions the study is for
Mycobacterium Ulcerans Infection
What is being tested?
Clarithromycin Extended Release and Streptomycin intramuscular injection
Could I receive a placebo?
No, everyone receives an active treatment
How many people
310 participants
Where
5 sitesin 2 countries
Study dates
Dec 2012to Jan 2018
Phase
Phase 2/3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 5 years and older
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 13Show fewer
  • 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

Trial locations and contacts

5 sites in 2 countries.

5 sites in 2 countries

Ghana4 sites

  • Agogo Presbyterian Hospital

    Agogo

  • Dunkwa Government Hospital

    Dunkwa-on-Offin

  • Nkawie-Toase Government Hospital

    Nkawie Panyin

  • Tepa Government Hosital

    Tepa

Other trials in Ghana

Benin1 site

  • Pobè Treatment Center

    Pobè

Other trials in Benin

About this study

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)

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.

Read more

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
Read the 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

Being tested
Clarithromycin Extended Release, Streptomycin intramuscular injection
Keywords
M. ulcerans, Buruli ulcer, drug trial, clarithromycin
Medical subject headings
Buruli Ulcer

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Clarithromycin Extended ReleaseDrug

    oral administration of Clarithromycin extended release

  • Streptomycin intramuscular injectionDrug

    daily intramuscular drug injection

Study groups in NCT01659437
Study groupRoleWhat they receive
SR8Active comparatorStreptomycin (S: 15 mg/kg per day, intramuscularly) in combination with rifampicin (R: 10 mg/kg per day, orally) for 8 weeks
Receives: Drug: Streptomycin intramuscular injection
CR8ExperimentalClarithromycin (C: 15 mg/kg per day, oral extended release formulation) in combination with rifampicin (10 mg/kg per day, orally) for 8 weeks
Receives: Drug: Clarithromycin Extended Release

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: 12 months after start of treatment

Secondary outcomes (12)

  1. Recurrence rate within 12 months of treatment initiation

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

    Measured: 12 months

  2. Rate of treatment failure within 12 months of treatment initiation

    proportion of treatment failure will be compared between groups

    Measured: 12 months

  3. 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

    Measured: 12 months

  4. 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?

    Measured: 12 months

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

    do lesions heal faster in one of the two treatments?

    Measured: 12 months

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

    Measured: 12 months

  7. Interval between healing and recurrence

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

    Measured: 12 months

  8. 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?

    Measured: 12 months

  9. 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?

    Measured: 12months

  10. Proportion of patients with residual functional limitations

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

    Measured: 12 months

  11. 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?

    Measured: 8 weeks

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

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

    Measured: 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 Aug 2012 (estimated)
  2. Study startDec 2012
  3. Primary completionDec 2017
  4. Study completionJan 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
310 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01659437
Sponsor's protocol ID
T9-370-1
Status last verified
Sep 2019
First submitted
2 Aug 2012
Last updated
26 Sep 2019
Results posted
No
Data monitoring committee
Yes
Individual data sharing
Yes: 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

Publications

  • 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.

    PubMed 20137805

  • 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.

    PubMed 21148526

  • 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.

    PubMed 21152060

  • 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.

    PubMed 22272368

  • 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.

    PubMed 32171422

  • 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.

    PubMed 30102705

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Clarithromycin Extended Release and Streptomycin intramuscular injection in people with Mycobacterium Ulcerans Infection, run by University Medical Center Groningen at 5 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 1 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 26 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in Ghana, Benin. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

healing without recurrence and without excision surgery (time frame: 12 months after start of treatment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01659437, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Sep 2019.

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