A Study to Evaluate the Efficacy and Safety of TMC207 in Patients With Pulmonary Infection With Multi-drug Resistant Mycobacterium Tuberculosis
A Study to Evaluate the Efficacy and Safety of TMC207 in Patients With Pulmonary Infection With Multi-drug Resistant Mycobacterium Tuberculosis
The purpose of this study is to provide safety and efficacy data for TMC207 and to
 demonstrate that TMC207 added to a background regimen (BR) is superior to treatment with the
 BR plus placebo.
This is a randomized (individuals will be assigned by chance to study treatments),
 double-blind (individual and investigator will not know the identity of study treatments),
 placebo (substance containing no active medication)-controlled, 2-arm study in patients with
 sputum smear-positive pulmonary infection with multi-drug resistant tuberculosis (MDR-TB)
 defined as tuberculosis (TB) due to infection with a strain of Mycobacterium tuberculosis (M.
 tuberculosis) that is resistant to both isoniazid and rifampin, or pre-extensively drug
 resistant (pre-XDR-TB) defined as TB due to infection with an MDR strain of M. tuberculosis
 that is resistant either to at least one of the injectable second-line drugs [amikacin,
 kanamycin, or capreomycin] or to any fluoroquinolone, but not both). Approximately 600
 patients with sputum smear-positive pulmonary infection with MDR-TB or pre-XDR TB will
 receive a background regimen (BR) of MDR-TB therapy and will be randomly assigned in a 1:1
 ratio to one of 2 treatment arms (Arms A [TMC207 + BR] and B [placebo + BR]). All patients
 will receive TMC207 or placebo in combination with a BR of MDR-TB therapy. TMC207 (or
 matching placebo) will be taken as oral tablets at a once daily dose of 400 mg for the first
 2 weeks and 200 mg 3 times/week for the remaining period of TMC207 (or matching placebo)
 administration. The study will consist of a screening phase of a maximum of 3 weeks, a
 36-week double-blind treatment phase, followed by a 48-week follow-up phase up to Week 84,
 also referred to as the treatment-free follow-up. After the treatment-free follow-up phase,
 there will be a safety follow-up phase of 48 weeks up to Week 132. Patients from Arms A or B
 who fail treatment according to prespecified criteria will be given the option to receive 24
 weeks of TMC207 plus an individualized salvage regimen taken for a duration consistent with
 national TB guidelines. Efficacy and pharmacokinetic evaluations will be performed at time
 points as detailed in the protocol. Safety will be monitored throughout the study.
Inclusion Criteria:

 - Diagnosed with sputum smear-positive pulmonary Mycobacterium multi-drug resistant
 tuberculosis; including pre-extensively drug resistant TB, and positive for acid fast
 bacilli on direct smear examination of expectorated or induced sputum specimen (>=1+ smear
 positive within the preceding 3 weeks) at screening and also on Day -1

 Exclusion Criteria:

 -  Has known infection with extensively drug resistant tuberculosis isolate

 -  Has a clinically significant active medical condition such as, but not limited to,
 hepatic, pancreatic, renal, cardiovascular, gastrointestinal, hematologic, neurologic,
 locomotor, immunologic, ophthalmologic (e.g., corneal opacification or ulcers,
 uveitis, chorioretinitis), metabolic (except stable diabetes based on the
 investigator's judgement), endocrine, oncological disease, muscular disease (e.g.,
 myositis, rhabdomyolysis), or psychiatric, dermatological illness, or any other
 illness that the investigator considers should exclude the patient or that could
 interfere with the interpretation of the study results. Eligibility of patients with
 poorly controlled diabetes as indicated by hemoglobin A1c higher than the normal range
 at screening should be based on the investigators judgment