Shortening Treatment by Advancing Novel Drugs
Condition: Tuberculosis, Pulmonary, Drug Sensitive; Tuberculosis, Pulmonary, Multi Drug-resistant
MeSH terms: Tuberculosis; Tuberculosis, Pulmonary; Hypersensitivity
Intervention: Moxifloxacin; PA-824; Pyrazinamide; HRZE (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol combination); HR (rifampicin plus isoniazid combination tablets)
Intervention description: Oral; Oral; Oral; Oral; Oral
Intervention MeSH terms: Moxifloxacin; Rifampin; Isoniazid; Pyrazinamide; Ethambutol
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 284.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Tuberculosis; Multi Drug-Resistant Tuberculosis; Drug-sensitive Tuberculosis; PA-824; Moxifloxacin; Pyrazinamide; Rifampicin; Isoniazid; Ethambutol; HRZE; HR; Pretomanid; NC-006; STAND

Summary:

      The purpose of this study is to assess the efficacy, safety and tolerability of a combination
      of moxifloxacin, PA-824, and pyrazinamide treatments with varying doses and treatment lengths
      from 4 to 6 months in subjects with drug-sensitive (DS) pulmonary TB compared to standard
      HRZE treatment.

      This study will also assess the efficacy, safety and tolerability of a combination of
      moxifloxacin, PA-824, and pyrazinamide treatments after 6 months of treatment in subjects
      with multi drug-resistant (MDR) pulmonary TB compared to a combination of moxifloxacin,
      PA-824, and pyrazinamide treatments in DS-TB subjects.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Signed written consent or witnessed oral consent in the case of illiteracy, prior to
             undertaking any trial-related procedures.

          2. Male or female, aged 18 years or over.

          3. Body weight (in light clothing and no shoes) ≥ 30 kg.

          4. Sputum positive for tubercule bacilli (at least 1+ on the International Union Against
             Tuberculosis and Lung Disease (IUATLD) and World Health Organization (WHO) scale on
             smear microscopy at the trial laboratory.

          5. Drug-Sensitive TB treatment arms subjects should be:

               -  sensitive to rifampicin by rapid sputum based test (may be sensitive or resistant
                  to isoniazid) AND

               -  either newly diagnosed for TB or have a patient history of being untreated for at
                  least 3 years after cure from a previous episode of TB. If they are entered into
                  the trial due to being sensitive to rifampicin by rapid sputum based test,
                  however on receipt of the rifampicin resistance testing using an indirect
                  susceptibility test in liquid culture this shows they are rifampicin resistant,
                  they will be:

               -  Excluded as late exclusions;

               -  Possibly replaced as determined by the sponsor.

          6. MDR-TB treatment arm subjects should be resistant to rifampicin by rapid sputum based
             test (may be sensitive or resistant to isoniazid).

          7. A chest x-ray which in the opinion of the investigator is compatible with pulmonary
             TB.

          8. Be of non-childbearing potential or using effective methods of birth control, as
             defined below:

        Non-childbearing potential:

          -  Subject - not heterosexually active or practice sexual abstinence; or

          -  Female subject or male subjects female sexual partner - bilateral oophorectomy,
             bilateral tubal ligation and/or hysterectomy or has been postmenopausal with a history
             of no menses for at least 12 consecutive months; or

          -  Male subject or female subjects male sexual partner - vasectomised or has had a
             bilateral orchidectomy minimally three months prior to screening;

        Effective birth control methods:

          -  Double barrier method which can include a male condom, diaphragm, cervical cap, or
             female condom; or

          -  Female subject: Barrier method combined with hormone-based contraceptives or an
             intra-uterine device for the female patient.

          -  Male subjects' female sexual partner: Double barrier method or hormone-based
             contraceptives or an intra-uterine device for the female partner.

        and are willing to continue practising birth control methods and are not planning to
        conceive throughout treatment and for 12 weeks (male subjects) or 1 week (female subjects)
        after the last dose of trial medication or discontinuation from trial medication in case of
        premature discontinuation.

        (Note: Hormone-based contraception alone may not be reliable when taking IMP; therefore,

        Exclusion Criteria:

          1. Any non TB related condition (including myasthenia gravis) where participation in the
             trial, as judged by the investigator, could compromise the well-being of the subject
             or prevent, limit or confound protocol specified assessments.

          2. Being or about to be treated for Malaria.

          3. Is critically ill and, in the judgment of the investigator, has a diagnosis likely to
             result in death during the trial or the follow-up period.

          4. TB meningitis or other forms of extrapulmonary tuberculosis with high risk of a poor
             outcome, or likely to require a longer course of therapy (such as TB of the bone or
             joint), as judged by the investigator.

          5. History of allergy or hypersensitivity to any of the trial IMP or related substances,
             including known allergy to any fluoroquinolone antibiotic, history of tendinopathy
             associated with quinolones or suspected hypersensitivity to any rifampicin
             antibiotics.

          6. For HIV infected subjects any of the following:

               -  CD4+ count <100 cells/µL;

               -  Karnofsky score <60%;

               -  Received intravenous antifungal medication within the last 90 days;

               -  WHO Clinical Stage 4 HIV disease.

          7. Resistant to fluoroquinolones (rapid, sputum - based molecular screening tests). If
             they are entered into the trial due to being sensitive to fluoroquinolones by rapid
             sputum based test, however on receipt of the fluoroquinolones resistance testing using
             an indirect susceptibility test in liquid culture this shows they are fluoroquinolones
             resistant, they will be:

               -  Excluded as late exclusions;

               -  Possibly replaced as determined by the sponsor.

          8. Resistant to pyrazinamide (rapid, sputum - based molecular screening tests).

             Drug-Sensitive TB treatment arms subjects may be entered prior to receipt of the
             rapid, sputum - based molecular pyrazinamide resistance screening test result. On
             receipt of the result, if they are resistant, they will be:

               -  Excluded as late exclusions;

               -  Possibly replaced as determined by the sponsor. MDR-TB treatment arm subjects may
                  not be entered prior to receipt of the rapid, sputum - based molecular
                  pyrazinamide resistance screening test result showing they are sensitive to
                  pyrazinamide.

          9. Having participated in other clinical trials with investigational agents within 8
             weeks prior to trial start or currently enrolled in an investigational trial.

         10. Subjects with any of the following at screening (per measurements and reading done by
             Central Electrocardiogram (ECG) where applicable):

               -  Cardiac arrhythmia requiring medication;

               -  Prolongation of QT/QTc interval with QTcF (Fridericia correction) >450 ms;

               -  History of additional risk factors for Torsade de Pointes, (e.g., heart failure,
                  hypokalemia, family history of Long QT Syndrome);

               -  Any clinically significant ECG abnormality, in the opinion of the investigator.

         11. Unstable Diabetes Mellitus which required hospitalization for hyper- or hypo-glycaemia
             within the past year prior to start of screening.

             Specific Treatments

         12. Previous treatment with PA-824 as part of a clinical trial.

         13. For DS-TB treatment arms: Previous treatment for tuberculosis within 3 years prior to
             Day (-9 to -1)(Screening). 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.

             For the MDR-TB Subjects: Previous treatment for MDR-TB, although may have been on a
             MDR TB treatment regimen for no longer than 7 days at start of screening.

             Previous treatment for TB includes, but is not limited to, gatifloxacin, amikacin,
             cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, rifapentine,
             thioacetazone, capreomycin, quinolones, thioamides, and metronidazole.

         14. 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.

         15. Use of any drug within 30 days prior to randomisation known to prolong QTc interval
             (including, but not limited to, amiodarone, amitriptyline, bepridil, chloroquine,
             chlorpromazine, cisapride, clarithromycin, disopyramide dofetilide, domperidone,
             droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl,
             mesoridazine, methadone, pentamidine, pimozide, procainamide, quinacrine, quinidine,
             sotalol, sparfloxacin, thioridazine).

         16. Use of systemic glucocorticoids within one year of start of screening (inhaled or
             intranasal glucocorticoids are allowed).

         17. Subjects recently started or expected to need to start anti-retroviral therapy (ART)
             within 1 month after randomization. Subjects may be included who have been on ARTs for
             greater than 30 days prior to start of screening, or who are expected to start ART
             greater than 30 days after randomization.

             Laboratory Abnormalities

         18. Subjects with the following toxicities at screening as defined by the enhanced
             Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November
             2007), where applicable:

               -  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;

               -  haemoglobin grade 4 (<6.5 g/dL);

               -  platelets grade 3 or greater (under 50x109 cells/L/ 50 000/mm3);

               -  serum potassium less than the lower limit of normal for the laboratory. This may
                  be repeated once;

               -  aspartate aminotransferase (AST) grade 3 or greater (≥3.0 x ULN) ;

               -  alanine aminotransferase (ALT) grade 3 or greater (≥3.0 x ULN);

               -  alkaline phosphatase (ALP):

                    -  grade 4 (>8.0 x ULN) to be excluded;

                    -  grade 3 (≥3.0 - 8.0 x ULN) must be discussed with and approved by the
                       sponsor Medical Monitor;

               -  total bilirubin:

                    -  2.0 x ULN, when other liver functions are in the normal range

                    -  1.50 x ULN when accompanied by any increase in other liver function tests
                       subjects with total bilirubin > 1.25 x ULN and accompanied by any increase
                       in other liver function tests must be discussed with the sponsor medical
                       monitor before enrollment