Evaluation of 8 Weeks of Treatment With the Combination of Moxifloxacin, PA-824 and Pyrazinamide in Patients With Drug Sensitive and Multi Drug-Resistant Pulmonary Tuberculosis (TB) (NC-002)

A Phase II Open-Label Partially Randomized Trial to Evaluate the Efficacy, Safety and Tolerability of the Combination of Moxifloxacin Plus PA-824 Plus Pyrazinamide After 8 Weeks of Treatment in Adult Patients With Newly Diagnosed Drug-Sensitive or Multi Drug-Resistant, Smear-Positive Pulmonary Tuberculosis

The purpose of this study is to assess the mycobactericidal activity of the moxifloxacin plus PA-824 plus pyrazinamide regimen after 8 weeks of treatment.

Inclusion Criteria:

• Provide written, informed consent prior to all trial-related procedures including HIV testing (if an HIV test was performed within 1 month prior to trial start, it should not be repeated as long as documentation can be provided [ELISA and/or Western Blot]).
• Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive.
• Sputum smear-positive pulmonary TB (at trial appointed laboratory). For Drug Sensitive TB treatment arms, subjects should be newly diagnosed and previously untreated. Exception: Participants can be included in the trial if they were diagnosed and treated for TB greater than 5 years prior to screening and can provide documentation of cure for that episode. Additionally, participants who have previously received H prophylactically can be included as long as that treatment is/was discontinued at least 7 days prior to randomization into this trial. Drug sensitive status to be confirmed with fluoroquinolone, rifampicin and isoniazid susceptibility testing at screening using Hain Plus rapid sputum test.

For the MDR-TB treatment arm only: Subjects with smear-positive MDR infection, defined as confirmed resistance to at least both R and H confirmed at screening for entry into this trial. Resistance to R and H will be determined using the rapid screen test (Hain Plus). If the first spot sputum shows an indeterminate result, the test must be repeated on freshly collected spot sputum or overnight sputum and that result may be used.

Subjects with newly diagnosed MDR-TB are defined as a) subjects with MDR-TB who have never been treated for TB before, or b) subjects with MDR-TB who have previously been treated with only one course of first-line TB drugs (H, R, E, Z and/or S) and that treatment is/was discontinued at least 7 days prior to randomization into this trial. Additionally, MDR-TB participants who have previously received H prophylactically can be included as long as that treatment is/was discontinued at least 7 days prior to randomization into this trial.

• A chest X-ray picture which in the opinion of the Investigator is compatible with TB.
• Sputum positive (at site laboratory) on direct microscopy for acid-fast bacilli (at least 1+ on the IUATLD/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: 1) of non-childbearing potential (have had a bilateral oophorectomy, tubal ligation and/or hysterectomy or have been postmenopausal for at least 12 consecutive months), 2) if they are using effective birth control methods and are willing to continue practicing birth control methods throughout treatment or 3) be non-heterosexually active, practice sexual abstinence 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 contraceptive measures until one week after the last dose of study medication or one week after discontinuation from study medication in case of premature discontinuation. (Note: Hormone-based contraception alone may not be reliable when taking IMP; therefore, hormone-based contraceptives alone cannot be used by female participants to prevent pregnancy).
• Male participants who are having heterosexual intercourse with females of child-bearing potential are required to use one of the following birth control methods during their participation in the trial and for 12 weeks after their last dose of study medication to prevent pregnancy:
• a double barrier method which can include a male condom, diaphragm, cervical cap, or female condom; or
• a barrier method combined with hormone-based contraceptives or an intra-uterine device for the female partner.

The use of the above mentioned birth control method does not apply if the male participant has been vasectomised or has had a bilateral orchidectomy minimally three months prior to screening, or is not heterosexually active, or practices sexual abstinence or if the female sexual partner has had a bilateral oophorectomy, tubal ligation and/or hysterectomy or has been postmenopausal for at least 12 consecutive months.

Exclusion Criteria:

• Evidence of clinically significant (as judged by the investigator), metabolic, gastrointestinal, cardiovascular, musculoskeletal, ophthalmological, pulmonary, neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities (other than the indication being studied) including myasthenia gravis and malaria.
• End stage liver failure (class Child Pugh C).
• Poor general condition where any delay in treatment cannot be tolerated per discretion of the Investigator.
• Clinically significant evidence of extrathoracic TB (e.g. miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis), as judged by the Investigator.
• History of allergy or hypersensitivity to any of the study IMP or related substances, including a known allergy to any fluoroquinolone antibiotic, history of tendinopathy associated with quinolones or suspected hypersensitivity to any rifamycin antibiotics.
• Resistance to fluoroquinolones (Hain plus rapid test) and/or pyrazinamide. Participants may be included in the study prior to receipt of the susceptibility test results for fluoroquinolones or pyrazinamide, however once these are received after a participant has entered into the study and if the results show the participant is resistant to fluoroquinolones and/or pyrazinamide, such a participant should be removed from the trial. DS participants will not be replaced, but MDR-TB participants taking part in the EBA Sub-Study could be replaced after consultation and written approval with the sponsor.
• Known (positive urine drug screen) or suspected, current or history of within the past 2 years, alcohol or drug abuse, that is, in the opinion of the Investigator, sufficient to compromise the safety or cooperation of the participant.
• For HIV infected participants:
• having a CD4+ count <200 cells/µL;
• or having received intravenous antifungal medication within the last 90 days;
• or with an AIDS-defining opportunistic infection or malignancies (except pulmonary TB).
• Having participated in other clinical study/ies with investigational agent/s within 8 weeks prior to trial start.
• Significant cardiac arrhythmia requiring medication.
• Participants with the following at screening (per measurements and reading done by Central ECG):
• Marked prolongation of QT/QTc interval, e.g., confirmed demonstration of QTcF (Fridericia correction) or QTcB (Bazett correction) 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 are known to prolong the QT/QTc interval (see exclusion criterion 21 as well as list of disallowed medication in the study protocol);
• Any clinically significant, in the opinion of the Investigator, ECG abnormality.
• Females who are pregnant, breast-feeding, or planning to conceive a child within one week of cessation of treatment.
• Males planning to conceive a child within twelve weeks of cessation of treatment.
• History and/or presence (or evidence) of neuropathy or epilepsy.
• Diabetes Mellitus requiring insulin.
• History of lens opacity or evidence of lens opacity on slit lamp ophthalmologic examination.
• Previously received treatment with PA-824 as part of a clinical trial.
• For the DS-TB treatment arms: treatment with any drug active against MTB within the 3 months prior to Visit 1 (e.g. isoniazid, ethambutol, amikacin, clofazimine, cycloserine, rifabutin, rifampicin, streptomycin, kanamycin, para-aminosalicylic acid, rifapentine, pyrazinamide, thioacetazone, capreomycin, fluoroquinolones, thioamides, metronidazole). Exceptions noted in Inclusion Criteria.
• For the MDR-TB Subjects: previously treated for MDR-TB. Defined as having received multiple courses of first-line therapy or any second-line TB drug, including any of the following anti-mycobacterials: any aminoglycoside except streptomycin, any fluoroquinolone, the thioamides, prothionamide or ethionamide and cycloserine.
• 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 allergy to any TB drug, their component or to the IMP.
• Any disease or conditions in which any of the medicinal products listed in the section of the protocol pertaining to prohibited medications is used.
• Use of any drug within 30 days prior to dosing known to prolong QTc interval (including amiodarone, bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine). Exceptions may be made for participants that have received 3 days or less of one of these drugs or substances, if there has been a wash-out period before administration of IMP equivalent to at least 5 half-lives of that drug or substance.
• Use of any therapeutic agents known to alter any major organ function (e.g., barbiturates, opiates, phenothiazines, cimetidine) within 30 days prior to dosing. The Investigator may choose at his/her discretion to make an exception for opiates or painkillers if they were part of prescribed medication for cough or underlying disease.
• Use of systemic glucocorticoids within one year prior to dosing.
• Participants 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]);
• creatinine clearance (CrCl) level less than 30 mls/min. according to the Cockcroft-Gault Formula;
• hemoglobin grade 4 (<6.5 g/dL);
• platelets grade 2 or greater (under 50x109 cells/L);
• serum potassium less than the lower limit of normal for the laboratory;
• aspartate aminotransferase (AST) grade 3 or greater (≥3.0 x ULN) to be excluded;
• alanine aminotransferase (ALT) grade 3 or greater (≥3.0 x ULN) to be excluded;
• alkaline phosphatase (ALP) grade 4 (>8.0 x ULN) to be excluded, grade 3 (≥3.0 - 8.0 x ULN) must be discussed with the sponsor Medical Monitor;
• total bilirubin grade 3 or greater (>2.0 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 sponsor Medical Monitor.