Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis With(J-M-Pa-Z)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Global Alliance for TB Drug Development
ClinicalTrials.gov Identifier:
NCT01215851
First received: October 5, 2010
Last updated: September 21, 2012
Last verified: September 2012

October 5, 2010
September 21, 2012
October 2010
May 2011   (final data collection date for primary outcome measure)
Extended early bactericidal activity (EBA) measured as the rate of change in log CFUs (colony forming units) in sputum. [ Time Frame: 14 consecutive days of treatment ] [ Designated as safety issue: No ]
Same as current
Complete list of historical versions of study NCT01215851 on ClinicalTrials.gov Archive Site
  • Standard EBA day 0-2 defined by change of CFU in sputum. [ Time Frame: Day 0-2 ] [ Designated as safety issue: No ]
  • Standard EBA day 2-14 defined by change of CFU in sputum [ Time Frame: Day 2-14 ] [ Designated as safety issue: No ]
  • Standard EBA day 7-14 defined by change of CFU in sputum [ Time Frame: Day 7-14 ] [ Designated as safety issue: No ]
  • Change in time to sputum culture positivity (TTP) [ Time Frame: 14 Days ] [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis With(J-M-Pa-Z)
A Phase II Trial to Evaluate the Early Bactericidal Activity, Safety and Tolerability of the Following: TMC207 Alone, TMC207 Plus Pyrazinamide,TMC207 Plus PA-824,PA-824 Plus Pyrazinamide and PA-824 Plus Pyrazinamide and Moxifloxacin, in Adult Patients With Newly Diagnosed, Smear-Positive Pulmonary Tuberculosis.

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.

Not Provided
Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Pulmonary Tuberculosis
  • Drug: PA-824
    200 mg tablet, once daily for 14 days
  • Drug: Pyrazinamide
    Dosed by Weight
  • Drug: TMC207
    TMC207 700 mg Day 1; 500mg Day 2; 400mg Days 3-14
  • Drug: Rifafour
    Rifafour e-275 275 mg
  • Drug: Moxifloxacin
    moxifloxacin 400 mg
  • Experimental: TMC207
    TMC207 700 mg Day 1; 500mg Day 2; 400mg Days 3-14 plus pyrazinamide placebo
    Intervention: Drug: TMC207
  • Experimental: TMC207 and pyrazinamide
    TMC207 700 mg Day 1; 500mg Day 2; 400mg Days 3-14 plus pyrazinamide (dosed by weight)
    Interventions:
    • Drug: Pyrazinamide
    • Drug: TMC207
  • Experimental: PA-824 and pyrzinamide
    PA-824 200mg and pyrazinmide (dosed by weight)and moxifloxacin placebo
    Interventions:
    • Drug: PA-824
    • Drug: Pyrazinamide
  • Experimental: PA-824 and moxifloxacin and pyrazinamide
    PA-824 200 mg and pyrazinamide (dosed by weight) and moxifloxacin 400 mg
    Interventions:
    • Drug: PA-824
    • Drug: Moxifloxacin
  • Active Comparator: Rifafour e-275 mg
    Rifafour e-275 275 mg
    Intervention: Drug: Rifafour
  • Experimental: TMC207 and PA-824
    TMC207 700 mg Day 1; 500mg Day 2; 400mg Days 3-14 plus PA-824 200 mg
    Interventions:
    • Drug: PA-824
    • Drug: TMC207
Diacon AH, Dawson R, von Groote-Bidlingmaier F, Symons G, Venter A, Donald PR, van Niekerk C, Everitt D, Winter H, Becker P, Mendel CM, Spigelman MK. 14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial. Lancet. 2012 Sep 15;380(9846):986-93. doi: 10.1016/S0140-6736(12)61080-0. Epub 2012 Jul 23.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
85
September 2011
May 2011   (final data collection date for primary outcome measure)

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.
Both
18 Years to 65 Years
No
Contact information is only displayed when the study is recruiting subjects
South Africa
 
NCT01215851
NC-001-(J-M-Pa-Z)
No
Global Alliance for TB Drug Development
Global Alliance for TB Drug Development
Not Provided
Principal Investigator: Andreas Diacon Karl Bremer Hospital, Cape Town South africa
Global Alliance for TB Drug Development
September 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP