Please select the eligibility criteria that correspond to the clinical trial below.
Title: Timing of the Decision on Surgical Intervention for Buruli Ulcer Patients Treated With Rifampicin/Streptomycin
Brief Summary: SUMMARY

Rationale: Buruli ulcer, caused by Mycobacterium ulcerans, is an ulcerative disease endemic in West Africa. It often leads to functional limitations. Treatment was by extensive surgery, until in 2005 gradually antibiotic treatment for eight weeks with rifampicin and streptomycin was added. Observation of Buruli ulcer lesions of limited size during antibiotic treatment showed that during treatment there is a paradoxical increase of the lesion, with a decrease of the lesion after week 14. Current WHO protocols advise to decide whether surgery is needed four weeks after the start of antibiotics. This might be too early in the healing process. The investigators hypothesize that delay in surgery is safe, and that it results in a reduction of the number of surgical interventions.

Objectives:

Primary Objective of this study is to compare the need for surgical treatment in standard timing of surgery at the end of eight weeks antimicrobial treatment with a policy to postpone surgical treatment until week 14.

Secondary Objectives are to study whether postponing surgery leads to less extensive surgery and a change in frequency of functional limitations;

Study design:

Patients will be randomized for surgery at week 8 after start of antibiotic treatment and week 14 after start of treatment. Reasons for treating doctors to decide to intervene with surgery will be according to current clinical practice and will be clearly defined in this protocol. Standard care of eight weeks of rifampicin and streptomycin will be given. All patients will be followed and lesional size using acetate sheet recordings will be used during follow-up.

Study population: Patients with a clinical picture of Buruli ulcer disease confirmed by diagnostic tests in the districts covered by the Buruli ulcer centers in Lalo and Allada, Benin. Patients who are pregnant, have a contraindication for general anaesthesia and children below three years old will be excluded. 130 Patients in each treatment arm will be included to detect a difference in percentage of patients needing surgery of 20 percent.

Main study parameters/endpoints: Primary outcome measure is the number of patients healed without surgery. Secondary outcome measures are the extent of surgery by measurement of lesional size, functional limitations after the end of treatment and one year after the start of treatment and the duration of admission.


Options:
A: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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).
B: 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
C: Inclusion Criteria:

1. Age 18 to 65 years
2. Clinical symptoms consistent with pulmonary TB and/or evidence of pulmonary TB on chest X-ray (CXR)
3. Sputum GeneXpert test positive
4. Willing to comply with the study visits and procedures
5. Resident at a fixed address
6. Willing to have directly observed therapy
7. Willing and able to provide written informed consent

Exclusion Criteria:

1. Taken more than 10 daily doses of standard anti-TB medication or fluoroquinolones during the 3 months prior to randomisation
2. Previous active TB disease for which treatment was given prior to the current episode
3. Known or suspected extra-pulmonary TB
4. Severe clinical pulmonary TB
5. Sputum smear 3+ on microscopy\*
6. Cavity size \> 4cm on screening CXR\*
7. Presence of rifampicin resistance on GeneXpert test
8. Poorly-controlled diabetes that, in the opinion of the investigator, is unlikely to be controlled with available management strategies
9. Active malignancy requiring systemic chemotherapy or radiotherapy
10. Known Hepatitis B surface antigen positive and/or HCV antibody positive, unless liver function tests consistently within normal range for at least 2 years
11. History of myocardial infarction, congestive cardiac failure, cardiac arrhythmias or any known congenital cardiac problems
12. History of severe chronic lung disease with symptom score of ≥3 on MRC breathlessness scale
13. History of seizures
14. Current tendinitis or history of tendinopathy associated with fluoroquinolone use
15. Symptomatic peripheral neuropathy causing greater than minimal interference with usual social and functional activities
16. Current alcohol or drug abuse
17. Women who are currently pregnant or breast-feeding
18. Women of childbearing potential unwilling or unable to use appropriate effective contraception for the first 6 months of the trial
19. Known allergy to one or more of the study drugs
20. Taking a concomitant medication that has a known or predicted interaction with any of the study drugs to which the patient might be randomised, or is known to prolong the QTc interval
21. Taking any immunosuppressive drugs or use of systemic corticosteroids for more than 2 weeks prior to screening
22. Colour blindness detected by Ishihara test

23.12-lead ECG at screening shows QTc greater than 450ms and/or any other clinically-significant abnormality such as arrhythmia or ischaemia

24.Any of the following laboratory parameters at screening:

* Absolute neutrophil \<1000 cells/mL, haemoglobin \<7.0 g/dL, OR platelet count \<50,000 cells/mm3
* Creatinine clearance of \<60ml/min (calculated using Cockcroft-Gault equation)
* ALT greater than 3 times the upper limit of normal
* Uncorrected serum potassium \<3.5 mmol/L

  25.HIV antibody positive at screening\*

  26.Any other significant condition (e.g. psychiatric illness, chronic diarrhoeal disease), that would, in the opinion of the investigator, compromise the patient's safety or outcome in the trial or lead to poor compliance with study visits and protocol requirements

  27.Participation in other clinical intervention trial or research protocol

Note: \*Criteria may be modified in later stages of the trial

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D: Inclusion Criteria:

* Patients with a clinical picture of Buruli ulcer disease in the districts covered by the Buruli ulcer centers in Lalo and Allada, Benin, will be included at start of antibiotic treatment.
* All stages of the disease will be included. Only patients with confirmed disease by direct microscopy following acid-fast staining or PCR will be included.

Exclusion Criteria:

* Patients not on the standard treatment of eight weeks of rifampicin and streptomycin for any reason, will be excluded from this study.
* Treatment with macrolide or quinolone antibiotics, or antituberculous medication, or immune-modulatory drugs including corticosteroids within the previous one month.
* Patients not compliant with the antibiotic therapy will be excluded as well. Non-compliance is defined as the use of \< 70 % of the prescribed antibiotics.
* Patients with a contraindication for general anaesthesia are not able to participate.
* Pregnancy.
* Osteomyelitis.
* Lesion close to the eye, with preferred standard treatment to wait for effect antibiotic treatment on extent surgery.
* The BUFLS (Buruli ulcer functional limitation score) cannot be applied to children below three years and therefore will not participate.
* Patients reporting to refuse surgery at any point in the intended treatment, cannot be included.
* Any situation or condition which may compromise ability to comply with the trial procedures.
* Patients known to be HIV positive.
* Lack of willingness to give informed consent (and/or assent by parent/legal representative).

Answer: D