Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis With(J-M-Pa-Z) (NC-001)
Condition: Pulmonary Tuberculosis
MeSH terms: Tuberculosis; Tuberculosis, Pulmonary
Intervention: PA-824; Pyrazinamide; TMC207; Rifafour; Moxifloxacin
Intervention description: 200 mg tablet, once daily for 14 days; Dosed by Weight; TMC207 700 mg Day 1; 500mg Day 2; 400mg Days 3-14; Rifafour e-275; moxifloxacin 400 mg
Intervention MeSH terms: Moxifloxacin; Pyrazinamide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 85.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Tuberculosis; EBA; TMC207; pretomanid; Early Bactericidal Activity; Pulmonary Tuberculosis; PA-824; bedaquiline; pyrazinamide; moxifloxacin; ethambutol; rifafour

Summary:

      The trial will evaluate the extended bactericidal activity of 14 consecutive days of oral
      administration of TMC207 alone, TMC207 with pyrazinamide, TMC207 with PA-824, PA-824 with
      pyrazinamide and PA-824 with moxifloxacin and pyrazinamide, as determined by the rate of
      change of log CFU in sputum over the time period Day 0-14 in participants with smear positive
      pulmonary tuberculosis (TB). A control group will receive standard treatment.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Provide written, informed consent prior to all trial-related procedures including HIV
             testing.

          2. Male or female, aged between 18 and 65 years inclusive.

          3. Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive.

          4. Newly diagnosed, previously untreated, sputum smear-positive pulmonary TB.

          5. A chest X-ray picture which in the opinion of the Investigator is compatible with TB.

          6. Sputum positive on direct microscopy for acid-fast bacilli (at least 1+ on the
             IUATLD/WHO scale).

          7. Ability to produce an adequate volume of sputum as estimated from a spot assessment
             (estimated 10 ml or more overnight production).

          8. Females may participate if they are: 1) of non-childbearing potential (have had a
             bilateral oophorectomy 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 6 months after the last dose of study
             medication or 6 months 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).

          9. 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 one month prior to
        screening, or is not heterosexually active, or practice sexual abstinence or if the female
        sexual partner has had a bilateral oophorectomy and/or hysterectomy or has been
        postmenopausal for at least 12 consecutive months.

        Exclusion Criteria

        Medical History

          1. 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).

          2. Poor general condition where any delay in treatment cannot be tolerated per discretion
             of the Investigator.

          3. A history of previous TB.

          4. Clinically significant evidence of extrathoracic TB (miliary TB, abdominal TB,
             urogenital TB, osteoarthritic TB, TB meningitis), as judged by the Investigator.

          5. History of allergy to the 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.

          6. Isoniazid-resistant and Rifampicin-resistant bacteria detected with a sputum specimen
             collected within the pre-treatment period and tested at the study laboratory.

          7. Known 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.

          8. HIV infected participants:

               1. having a CD4+ count <300 cells/µL;

               2. or having received antiretroviral therapy medication within the last 90 days;

               3. or having received oral or intravenous antifungal medication within the last 90
                  days;

               4. or with an AIDS-defining opportunistic infection or malignancies (except
                  pulmonary TB).

          9. Having participated in other clinical studies with investigational agents within 8
             weeks prior to trial start.

         10. Significant cardiac arrhythmia requiring medication.

         11. Participants with the following at screening:

               1. Marked prolongation of QT/QTc interval, e.g., confirmed demonstration of QTcF
                  (Fridericia correction) or QTcB (Bazett correction) interval >450 ms at
                  screening;

               2. History of additional risk factors for Torsade de Pointes, e.g., heart failure,
                  hypokalemia, family history of Long QT Syndrome;

               3. Use of concomitant medications that prolong the QT/QTc interval (see exclusion
                  criterion 22 as well as list of disallowed medication in Section 4.7.2);

               4. Pathological Q waves (defined as >40ms or depth >0.4-0.5mV);

               5. ECG evidence of ventricular pre-excitation;

               6. ECG evidence of complete or incomplete left bundle branch block or right bundle
                  branch block;

               7. ECG evidence of second or third degree heart block;

               8. Intraventricular conduction delay with QRS duration >120ms;

               9. Bradycardia as defined by sinus rate <50bpm.

         12. Females who are pregnant, breast-feeding, or planning to conceive a child within 6
             months of cessation of treatment.

         13. Males planning to conceive a child within twelve weeks of cessation of treatment.

         14. History and/or presence (or evidence) of neuropathy or epilepsy.

         15. Diabetes Mellitus requiring insulin.

         16. History of lens opacity or evidence of lens opacity on slit lamp ophthalmologic
             examination.

         17. For males, any evidence or history of a clinically significant abnormality in the
             reproductive system, including but not limited to the following: serum testosterone,
             luteinizing hormone (LH), and/or follicle-stimulating hormone (FSH) levels outside the
             laboratory reference range. An evaluation resulting in an isolated abnormal value
             (i.e., only 1 of the 3 hormones is abnormal) may be repeated using a morning (ideally,
             8am) serum specimen. If the laboratory value on the repeat specimen is outside the
             laboratory reference range, unless the result is deemed not clinically significant by
             the Investigator in consultation with the Sponsor Medical Monitor, the participant
             should be excluded.

             Specific Treatments

         18. Previously received treatment with TMC207 or PA-824 as part of a clinical trial.

         19. Treatment received with any drug active against MTB within the 3 months prior to Visit
             1 (e.g. isoniazid, ethambutol, amikacin, cycloserine, rifabutin, rifampicin,
             streptomycin, kanamycin, para-aminosalicylic acid, rifapentine, pyrazinamide,
             thioacetazone, capreomycin, fluoroquinolones, thioamides, metronidazole).

         20. 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.

         21. Any disease or conditions in which any of the medicinal products listed in the section
             pertaining to prohibited medications is used.

         22. Concomitant use of any drug 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). The exception is moxifloxacin which
             is one of the drugs being evaluated in this study, with extensive ECG monitoring to
             help ensure patient safety.

         23. Use of any drugs or substances within 30 days prior to dosing known to be strong
             inhibitors or inducers of cytochrome P450 enzymes (such as quinidine, tyramine,
             ketoconazole, testosterone, quinine, gestodene, metyrapone, phenelzine, doxorubicin,
             troleandomycin, cyclobenzaprine, erythromycin, cocaine, furafylline, cimetidine,
             dextromethorphan). 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.

         24. Use of any therapeutic agents known to alter any major organ function (e.g.,
             barbiturates, opiates, phenothiazines, cimetidine) within 30 days prior to dosing.

         25. Use of systemic glucocorticoids within one year prior to dosing.

             Based on Laboratory Abnormalities

         26. Participants with the following toxicities at screening as defined by the enhanced
             Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November
             2007):

               1. creatinine grade 2 or greater (>1.5 times upper limit of normal [ULN]);

               2. lipase grade 3 or greater (>2.0 x ULN);

               3. hemoglobin grade 4 (<6.5 g/dL);

               4. platelets grade 2 or greater (under 50x109 cells/L);

               5. serum potassium grade 2 or greater (<3.5 mEq/L);

               6. aspartate aminotransferase (AST) grade 3 (≥3.0 x ULN) to be excluded;

               7. alanine aminotransferase (ALT) grade 3 (≥3.0 x ULN) to be excluded;

               8. alkaline phosphatase (ALP) grade 4 (>8.0 x ULN) to be excluded, grade 3 (≥3.0 x
                  ULN) must be discussed with the sponsor Medical Monitor;

               9. 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.