A Phase 2 to Evaluate the Efficacy, Safety and Tolerability of Combinations of Bedaquiline, Moxifloxacin, PA-824 and Pyrazinamide in Adult Subjects With Drug-Sensitive or Multi Drug-Resistant Pulmonary Tuberculosis.

Inclusion Criteria

• Provide written, informed consent prior to all trial-related procedures. Male or female, aged between 18 and 75 years inclusive.
• Body weight (in light clothing and with no shoes) between 35 and 100 kg, inclusive.
• Tested at the trial appointed laboratory: M. Tb positive on molecular test (e.g. GeneXpert or Hain) and sputum smear-positive pulmonary TB on direct microscopy for acid-fast bacilli (at least 1+ on the IUATLD/WHO scale.
• For DS-TB treatment arms (defined as sensitive to rifampicin based on molecular sensitivity testing), Subjects should be:
• either newly diagnosed or untreated for at least 3 years after cure from a previous episode (Subject can give a history of cure and previous treatment); AND
• Previous TB treatment must be discontinued as per exclusion criteria 16.
• For MDR-TB treatment arm (defined as resistant to rifampicin based on molecular sensitivity testing), Subjects should be:
• sensitive to moxifloxacin by molecular sensitivity testing; AND
• either newly diagnosed or could have previously been treated for DS-TB and/or MDR-TB ( 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 are known to prolong the QT/QTc interval (see exclusion criteria 19);
• Any clinically significant, in the opinion of the Investigator, ECG abnormality.
• Females who are pregnant, breast-feeding, or planning to conceive a child during the study or within 6 months of cessation of treatment. Males planning to conceive a child during the study or within 6 months of cessation of treatment.
• Diabetes Mellitus resulting in hospitalization in the past year.
• Evidence of lens opacity on slit lamp ophthalmologic examination as defined by a grading of >1+ on the AREDS2 grading system.
• For males, any history of a clinically significant abnormality in the reproductive system.

Specific Treatments

• Previously received treatment with PA-824, bedaquiline or moxifloxacin as part of a clinical trial.
• For the DS-TB treatment arms: treatment with any drug active against M. Tb within the 3 years prior to Day 1 (including but not limited to isoniazid, ethambutol, amikacin, bedaquiline, clofazimine, cycloserine, fluoroquinolones, rifabutin, rifampicin, streptomycin, kanamycin, para-aminosalicylic acid, rifapentine, pyrazinamide, thioacetazone, capreomycin, thioamides, metronidazole). Exceptions include the use of fluoroquinolones and metronidazole as short-term treatment (≤2 weeks) for Non-M.Tb infections. Treatment should have been discontinued at least 3 months prior to Day 1. Subjects who have previously received isoniazid prophylactically may be included in the trial as long as that treatment is/was discontinued at least 7 days prior to randomization into this trial.
• MDR-TB Subjects may have previously been treated for DS-TB with first-line TB drugs (isoniazid, rifampicin, ethambutol, pyrazinamide and/or streptomycin) and/or received ≤7 days MDR-TB treatment, provided that treatment is/was discontinued at least 7 days prior to randomization. It should be confirmed that the MDR-TB treatment can be safely stopped and the screening period is long enough to allow for a washout period of 5 times the longest half-life of the drugs.
• Any diseases or conditions in which the use of the standard TB drugs or any of their components is contra-indicated, including but not limited to acute gout, allergy to any TB drug, their component or to the IMP.
• Use of any drug within 30 days prior to dosing known to prolong QTc interval (including but not limited to amiodarone, bepridil, chloroquine, chlorpromazine, cisapride, cyclobenzaprine, clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, sotalol, sparfloxacin