Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis With Clofazimine (C)-TMC207 (J)-PA-824 (Pa)-Pyrazinamide (Z)
Condition: Pulmonary Tuberculosis
MeSH terms: Tuberculosis; Tuberculosis, Pulmonary
Intervention: TMC207 (J); PA-824 (PA); pyrazinamide (Z); clofazimine (C); Rifafour
Intervention description: TMC207 400 mg Day 1; 300mg Day 2; 200mg Days 3-14; PA-824 200mg Days 1-14; 1500mg Days 1-14 Dosed by Weight; clofazimine 300mg Days 1-3 and clofazimine 100mg Days 4-14; Rifafour e-275 mg dosed by weight
Intervention MeSH terms: Pyrazinamide; Clofazimine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Enrollment: 105.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Tuberculosis; EBA; PA824; pretomanid; TMC207

Summary:

      The trial will evaluate the extended bactericidal activity of 14 consecutive days of oral
      administration of TMC207 plus PA-824 plus Pyrazinamide plus Clofazimine, TMC207 plus PA-824
      plus Pyrazinamide, TMC207 plus PA-824 plus Clofazimine alone, TMC207 plus Pyrazinamide plus
      Clofazimine, Pyrazinamide alone, Clofazimine alone, and standard first line TB treatment as
      per South African TB Guidelines (Rifafour e-275) as determined by the rate of change of log
      CFU per ml 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 GeneXpert or TB Smear from TB clinic or site initial diagnosis

             7. Sputum positive on direct microscopy for acid-fast bacilli (at least 1+ on the
             IUATLD/WHO scale).

             8. Ability to produce an adequate volume of sputum as estimated from a spot assessment
             (estimated 10 ml or more overnight production).

             9. Be of non-childbearing potential or using an effective method of birth control as
             defined as:

        Non-childbearing potential:

          1. Subject - Not heterosexually active or practice sexual abstinence or

          2. Female subject/sexual 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

          3. Male subject/sexual partner - vasectomised or has had a bilateral orchidectomy
             minimally three month prior to screening

        Effective birth control methods:

          1. Double barrier method which can include a male condom, diaphragms, cervical cap, or
             female condom or

          2. Barrier method combined with hormone based contraceptives or an intra-uterine device
             for the female partner and are willing to continue practicing birth control methods
             throughout treatment and for 12 weeks (male participants) or 6 months (female
             participants) after the last dose of study medication or 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).

        Exclusion Criteria:

          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) including malaria.

          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.

          6. Isoniazid-resistant and/or 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 <200 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. For ECGs, central cardiology overread
             and the mean of triplicate reading must be used:

               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 19 and disallowed medications;

               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. Males planning to conceive a child within twelve
             weeks of cessation of treatment.

         13. Diabetes Mellitus requiring insulin.

         14. History of lens opacity.

         15. For males, any history of a clinically significant abnormality in the reproductive
             system.

             Specific Treatments

         16. Previously received treatment with Clofazimine, TMC207 or PA-824.

         17. Treatment received with any drug active against MTB within the 3 months prior to Visit
             1 (e.g. isoniazid, ethambutol, amikacin, cycloserine, fluoroquinolones, rifabutin,
             rifampicin, streptomycin, kanamycin, para-aminosalicylic acid, rifapentine,
             pyrazinamide, thioacetazone, capreomycin, thioamides, metronidazole).

         18. 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.

         19. Concomitant use of any drug known to prolong QTc interval (including amiodarone,
             bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, cyclobenzaprine,
             disopyramide dofetilide, domperidone, droperidol, erythromycin, halofantrine,
             haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide,
             procainamide, quinidine, sotalol, sparfloxacin, thioridazine).

         20. 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.

         21. Use of any therapeutic agents known to alter any major organ function (e.g.,
             barbiturates, opiates, phenothiazines, cimetidine) within 30 days prior to dosing.
             Exceptions for opiate and pain killer use for cough or underlying disease may be made
             at investigator discretion.

             Based on Laboratory Abnormalities

         22. 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.