Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis (TMC207-CL001)

Inclusion criteria

• Provide written, informed consent prior to all trial-related procedures including HIV testing.
• Male or female, aged between 18 and 65 years inclusive.
• Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive.
• Newly diagnosed, previously untreated, uncomplicated, sputum smear-positive, pulmonary TB.
• A chest X-ray picture which in the opinion of the Investigator is compatible with TB.
• Sputum positive on direct microscopy for acid-fast bacilli …(at least 1+ on the International Union Against Tuberculosis and Lung Disease (IUATLD)/World Health Organization (WHO) scale).
• Ability to produce an adequate volume of sputum as estimated from a spot assessment (estimated 10 ml or more overnight production).
• Females may participate if they are of non-childbearing potential, if they are using effective birth control methods and are willing to continue practicing birth control methods throughout treatment or if they are non-heterosexually active or willing to practice sexual abstinence throughout the treatment period or have a vasectomized partner (confirmed sterile). Therefore to be eligible for this study women of childbearing potential should either:1) use a double barrier method to prevent pregnancy (i.e. use a condom with either diaphragm or cervical cap) or 2) use hormonal based contraceptives in combination with a barrier contraceptive, or 3) use an intrauterine device in combination with a barrier contraceptive. They must also be willing to continue these contraception until 6 months after last study drug or 6 months after discontinuation from study medication in case of premature discontinuation. (Note: Hormone-based contraception may not be reliable when taking TMC207; therefore, hormone-based contraceptives cannot be used by female patients to prevent pregnancy).
• Male patients must be willing to use a condom with spermicide when having heterosexual intercourse throughout treatment and until 1 month after last study drug administration or 1 month after discontinuation from study medication in case of premature discontinuation.

Exclusion criteria

• Evidence of clinically significant metabolic, gastrointestinal neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities (other than the indication being studied).
• Known or suspected hypersensitivity to study medications (including any rifamycin antibiotics)
• Rifampicin-resistant and/or isoniazid-resistant bacteria detected with a sputum specimen collected within the pre-treatment period and tested at the study laboratory.
• Clinically significant evidence of extrathoracic TB (miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis), as judged by the investigator.
• Current or past history of alcohol and/or drug use that, in the investigator's opinion, would compromise the participant's safety or compliance to the study protocol procedures.
• HIV infected patients:

• having a cluster of differentiation 4 (CD4)+ count <300 cells/µL;
• or having received antiretroviral therapy medication within the last 90 days:
• or having received oral or intravenous antifungal medication within the last 90 days;
• or with an AIDS-defining opportunistic infection or malignancies (except pulmonary TB).
• Significant cardiac arrhythmia requiring medication
• Having participated in other clinical studies with investigational agents within 8 weeks prior to trial start.
• Patients with the following QT/corrected QT(QTc) interval characteristics at screening:

• Marked prolongation of QT/QTc interval, e.g., confirmed demonstration of QT corrected for heart rate using Fridericia's method (QTcF) interval >450 ms at screening;
• History of additional risk factors for Torsade de Pointes, e.g., heart failure, hypokalemia, family history of Long QT Syndrome;
• Use of concomitant medications that prolong the QT/QTc interval listed as disallowed medication in Section 2.10.2;
• Pathological Q waves (defined as >40ms or depth >0.4-0.5mV);
• Evidence of ventricular pre-excitation;
• ECG evidence of complete or incomplete left bundle branch block or right bundle branch block;
• Evidence of second or third degree heart block;
• Intraventricular conduction delay with QRS duration >120ms;
• Bradycardia as defined by sinus rate <50bpm
• Women who are pregnant or breastfeeding
• History and/or presence (or evidence) of neuropathy or epilepsy.
• Diabetics using insulin
• Poor general condition where any delay in treatment cannot be tolerated per discretion of Investigator.
• Previously received treatment with TMC207 as part of a clinical trial.
• Treatment received with any drug active against Mycobacterium tuberculosis within 3 months prior to Visit 1.
• Any disease or conditions in which any of the medicinal products listed in the section pertaining to prohibited medications is used.
• Patients with the following toxicities at screening as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November 2007):

• creatinine grade 2 or greater (>1.5 times upper limit of normal [ULN]);
• lipase grade 3 or greater (>2.0 x ULN);
• hemoglobin grade 4 (<6.5 g/dL) except after discussion with the Medical Monitor;
• aspartate aminotransferase (AST) grade 4 (>8.0 x ULN) to be excluded, grade 3 (≥3.0 x ULN) must be discussed with Medical Monitor;
• alanine aminotransferase (ALT) grade 4 (>8.0 x ULN) to be excluded, grade 3 (≥3.0 x ULN) must be discussed with Medical Monitor;
• alkaline phosphatase (ALP) grade 4 (>8.0 x ULN) to be excluded, grade 3 (≥3.0 x ULN) must be discussed with Medical Monitor;
• total bilirubin grade 3 or greater (>2.00 x ULN, or >1.50 x ULN when accompanied by any increase in other liver function test) to be excluded, grade 2 (>1.50 x ULN, or >1.25 x ULN when accompanied by any increase in other liver function test) must be discussed with the Medical Monitor