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Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis With Clofazimine (C)-TMC207 (J)-PA-824 (Pa)-Pyrazinamide (Z) (NC-003)

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ClinicalTrials.gov Identifier: NCT01691534
Recruitment Status : Completed
First Posted : September 24, 2012
Results First Posted : December 13, 2016
Last Update Posted : December 13, 2016
Sponsor:
Information provided by (Responsible Party):
Global Alliance for TB Drug Development

Tracking Information
First Submitted Date  ICMJE September 20, 2012
First Posted Date  ICMJE September 24, 2012
Results First Submitted Date  ICMJE October 19, 2016
Results First Posted Date  ICMJE December 13, 2016
Last Update Posted Date December 13, 2016
Study Start Date  ICMJE October 2012
Actual Primary Completion Date April 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 19, 2016)
Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 0-14). [ Time Frame: 14 consecutive days of treatment ]
Original Primary Outcome Measures  ICMJE
 (submitted: September 20, 2012)
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 ]
Change History Complete list of historical versions of study NCT01691534 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 19, 2016)
  • EBA Measured as the Daily Rate of Change in log10 CFUs of M. Tuberculosis in Sputum on Solid Media (Days 0-2) [ Time Frame: Days 0-2 ]
  • EBA Measured as the Daily Rate of Change in log10 CFUs of M. Tuberculosis in Sputum on Solid Media (Days 7-14) [ Time Frame: Day 7-14 ]
  • EBA Expressed as the Daily Percentage Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 0-14) [ Time Frame: Days 0-14 ]
  • EBA Expressed as the Daily Percentage Change in TTP Signal in Liquid Culture for M. Tuberculosis (Day 0-2) [ Time Frame: Day 0-2 ]
  • EBA Expressed as the Daily Percentage Change in TTP Signal in Liquid Culture for M. Tuberculosis (Days 7-14) [ Time Frame: Days 7-14 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: September 20, 2012)
  • Standard EBA day 0-2 defined by change of CFU in sputum. [ Time Frame: Days 0-2 ]
  • Standard EBA day 7-14 defined by change of CFU in sputum [ Time Frame: Day 7-14 ]
  • EBA change in time to sputum culture positivity (TTP) day 0-2 [ Time Frame: Day 0-2 ]
  • EBA change in time to sputum culture positivity (TTP) days 0-14 [ Time Frame: 0-14 Days ]
  • EBA change in time to sputum culture positivity (TTP) days 7-14 [ Time Frame: 7-14 Days ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis With Clofazimine (C)-TMC207 (J)-PA-824 (Pa)-Pyrazinamide (Z)
Official Title  ICMJE A Phase 2 Trial to Evaluate the Early Bactericidal Activity, Safety and Tolerability of the Following: 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, and Clofazimine Alone; in Adult Patients With Newly Diagnosed, Smear-Positive Pulmonary Tuberculosis.
Brief 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Pulmonary Tuberculosis
Intervention  ICMJE
  • Drug: TMC207 (J)
    TMC207 400 mg Day 1; 300mg Day 2; 200mg Days 3-14
  • Drug: PA-824 (PA)
    PA-824 200mg Days 1-14
  • Drug: pyrazinamide (Z)
    1500mg Days 1-14 Dosed by Weight
  • Drug: clofazimine (C)
    clofazimine 300mg Days 1-3 and clofazimine 100mg Days 4-14
  • Drug: Rifafour
    Rifafour e-275 mg dosed by weight
Study Arms  ICMJE
  • Experimental: TMC207, PA-824, pyrazinamide and clofazimine (J-PA-Z-C)
    TMC207 400 mg Day 1; 300mg Day 2; 200mg Days 3-14 plus PA-824 200mg Days 1-14 plus pyrazinamide 1500mg Days 1-14 plus clofazimine 300mg Days 1-3 and Clofazamine 100mg Days 4-14
    Interventions:
    • Drug: TMC207 (J)
    • Drug: PA-824 (PA)
    • Drug: pyrazinamide (Z)
    • Drug: clofazimine (C)
  • Experimental: TMC207, PA-824 and pyrazinamide (J-PA-Z)
    TMC207 400 mg Day 1; 300mg Day 2; 200mg Days 3-14 plus PA-824 200mg Days 1-14 plus pyrazinamide 1500mg Days 1-14
    Interventions:
    • Drug: TMC207 (J)
    • Drug: PA-824 (PA)
    • Drug: pyrazinamide (Z)
  • Experimental: TMC207, PA-824 and clofazimine (J-PA-C)
    TMC207 400 mg Day 1; 300mg Day 2; 200mg Days 3-14 plus PA-824 200mg Days 1-14 plus clofazimine 300mg Days 1-3 and clofazimine 100mg Days 4-14
    Interventions:
    • Drug: TMC207 (J)
    • Drug: PA-824 (PA)
    • Drug: clofazimine (C)
  • Experimental: TMC207, pyrazinamide and clofazimine (J-Z-C)
    TMC207 400 mg Day 1; 300mg Day 2; 200mg Days 3-14 plus pyrazinamide 1500mg Days 1-14 plus clofazimine 300mg Days 1-3 and Clofazimine 100mg Days 4-14
    Interventions:
    • Drug: TMC207 (J)
    • Drug: pyrazinamide (Z)
    • Drug: clofazimine (C)
  • Experimental: pyrazinamide (Z)
    pyrazinamide 1500mg Days 1-14
    Intervention: Drug: pyrazinamide (Z)
  • Experimental: clofazimine (C)
    Clofazimine 300mg Days 1-3 and Clofazimine 100mg Days 4-14
    Intervention: Drug: clofazimine (C)
  • Active Comparator: Rifafour
    Rifafour e-275 mg dosed by weight
    Intervention: Drug: Rifafour
Publications * Diacon AH, Dawson R, von Groote-Bidlingmaier F, Symons G, Venter A, Donald PR, van Niekerk C, Everitt D, Hutchings J, Burger DA, Schall R, Mendel CM. Bactericidal activity of pyrazinamide and clofazimine alone and in combinations with pretomanid and bedaquiline. Am J Respir Crit Care Med. 2015 Apr 15;191(8):943-53. doi: 10.1164/rccm.201410-1801OC.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 20, 2012)
105
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE May 2013
Actual Primary Completion Date April 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE South Africa
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01691534
Other Study ID Numbers  ICMJE NC-003-(C-J-Pa-Z)
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Global Alliance for TB Drug Development
Study Sponsor  ICMJE Global Alliance for TB Drug Development
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Andreas Diacon, MD Karl Bremer Hospital, Cape Town South Africa
PRS Account Global Alliance for TB Drug Development
Verification Date August 2016

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