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A Phase 2 Open Label Partially Randomized Trial to Evaluate the Efficacy, Safety and Tolerability of Combinations of Bedaquiline, Moxifloxacin, PA-824 and Pyrazinamide in Adult Subjects With Drug-Sensitive or Multi Drug-Resistant Pulmonary Tuberculosis. (NC-005)

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02193776
First Posted: July 18, 2014
Last Update Posted: June 30, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Global Alliance for TB Drug Development
  Purpose
The purpose of this study is to determine the mycobactericidal activity of combinations of bedaquiline (J), moxifloxacin (M), PA-824 (Pa) and pyrazinamide (Z) regimens during 8 weeks of treatment.

Condition Intervention Phase
Tuberculosis Drug: Pa-824 Drug: bedaquiline Drug: moxifloxacin Drug: pyrazinamide Drug: isoniazid, rifampicin, pyrazinamide and ethambutol combination tablet Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Open-Label Partially Randomized Trial to Evaluate the Efficacy, Safety and Tolerability of Combinations of Bedaquiline, Moxifloxacin, PA-824 and Pyrazinamide During 8 Weeks of Treatment in Adult Subjects With Newly Diagnosed Drug-Sensitive or Multi Drug-Resistant, Smear-Positive Pulmonary Tuberculosis.

Resource links provided by NLM:


Further study details as provided by Global Alliance for TB Drug Development:

Primary Outcome Measures:
  • The Bactericidal Activity as determined by the rate of change in time to sputum culture positivity, Days 0 - 56. [ Time Frame: 8 weeks. Prior to the initial dose on days -2 and -1, and following the initial dose, on days 1,3,7,14,21,28,35,42,49, and 56. ]
    The Bactericidal Activity (BA,TTP[0-56]) as determined by the rate of change in time to sputum culture positivity (TTP) over 8 weeks of treatment in the Mycobacterial Growth Indicator Tube system, represented by the model-fitted log(TTP) results as calculated by the regression of the observed log(TTP) results over time.


Secondary Outcome Measures:
  • The Bactericidal Activity as determined by the rate of change in time to sputum culture positivity, Days 0 - 2. [ Time Frame: 2 days. Prior to the initial dose on days -2 and -1, and following the initial dose, on days 1 and 3. ]
    The Bactericidal Activity (BA,TTP[0-2]) as determined by the rate of change in time to sputum culture positivity (TTP) over Days 0 to 2 represented by the model-fitted log(TTP) as calculated by the regression of the observed log(TTP) counts over time.

  • The Bactericidal Activity as determined by the rate of change in time to sputum culture positivity, Days 14 - 56. [ Time Frame: 42 days. Days 14,21,28,35,42,49, and 56 after the initial dose. ]
    The Bactericidal Activity (BA,TTP[14-56]) as determined by the rate of change in time to sputum culture positivity (TTP) over Days 14 to 56 of treatment, represented by the model-fitted log(TTP) as calculated by the regression of the observed log(TTP) counts over time.

  • The Bactericidal Activity as determined by the rate of change in colony forming units, Days 0 - 56. [ Time Frame: 56 days. Prior to the initial dose on days -1 and -2, and post-dose on days 1,3,7,14,21,28,35,42,49, and 56. ]
    The Bactericidal Activity (BA,CFU[0-56]) as determined by the rate of change in colony forming units (CFU) over 8 weeks of treatment represented by the model-fitted log(CFU) results as calculated by the regression of the observed log(CFU) results over time.

  • The Bactericidal Activity as determined by the rate of change in colony forming units, Days 0 - 2. [ Time Frame: 2 days. Prior to the initial dose on days -1 and -2, and following the initial dose, on days 1 and 3. ]
    The Bactericidal Activity (BACFU[0-2]) as determined by the rate of change in colony forming units (CFU) over 8 weeks of treatment represented by the model-fitted log(CFU) results as calculated by the regression of the observed log(CFU) results over time.

  • The Bactericidal Activity as determined by the rate of change in colony forming units, Days 14 - 56. [ Time Frame: 42 days. Days 14,21,28,35,42,49, and 56 after the initial dose. ]
    The Bactericidal Activity (BACFU[14-56]) as determined by the rate of change in colony forming units (CFU) over 8 weeks of treatment represented by the model-fitted log(CFU) results as calculated by the regression of the observed log(CFU) results over time.

  • Time to sputum culture conversion using data from solid media, Days 0 - 56. [ Time Frame: 56 days. Prior to the initial dose on days -1 and -2, and post-dose on days 1,3,7,14,21,28,35,42,49, and 56. ]
    Time to sputum culture conversion using data from weekly solid media (Löwenstein-Jensen medium) cultures through 8 weeks of treatment.

  • Time to sputum culture conversion using data from liquid media, Days 0 - 56. [ Time Frame: 56 days. Prior to the initial dose on days -1 and -2, and post-dose on days 1,3,7,14,21,28,35,42,49, and 56. ]
    Time to sputum culture conversion using data from weekly cultures through 8 weeks of treatment using liquid (Mycobacterial Growth Indicator Tube) media.

  • Pharmacokinetic analysis of Ctrough of Investigational Medicinal Products, Days 0 - 70. [ Time Frame: 70 days. Samples will be collected pre-dose on Days 1, 4, 8, 15, 22, 29, 36, 43, 50 and during the site visit on Days 57 and 70. ]
    The lowest (trough) concentration before the next dose is administered of bedaquiline, bedaquiline metabolite M2, Pa-824, and pyrazinamide [DS-TB subjects in arms J(loading dose/t.i.w.)PaZ and J(200mg)PaZ) and MDR-TB arm J(200mg)MPaZ]. The trough concentration will also be measured for moxifloxacin in the MDR-TB J(200mg)MPaZ arm and pyrazinamide in the DS-TB HRZE arm.


Enrollment: 240
Study Start Date: November 2014
Estimated Study Completion Date: March 2018
Primary Completion Date: February 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: DS-TB: J(loading dose/t.i.w.)PaZ
Subjects with DS-TB. J(loading dose/t.i.w.)PaZ: Bedaquiline 400mg once daily Days 1-14, 200mg three times per week Days 15-56; plus PA-824 200mg once daily Days 1-56; plus pyrazinamide 1500mg once daily Days 1-56.
Drug: Pa-824
oral
Drug: bedaquiline
oral
Other Names:
  • TMC207
  • Sirturo
Drug: pyrazinamide
oral
Experimental: DS-TB: J(200mg)PaZ
Subjects with DS-TB. J(200mg)PaZ: Bedaquiline 200mg once daily Days 1-56; plus PA-824 200mg once daily Days 1-56; plus pyrazinamide 1500mg once daily Days 1-56.
Drug: Pa-824
oral
Drug: bedaquiline
oral
Other Names:
  • TMC207
  • Sirturo
Drug: pyrazinamide
oral
Experimental: MDR-TB: J(200mg)MPaZ
Subjects with MDR-TB. J(200mg)MPaZ: Bedaquiline 200mg once daily Days 1-56; plus moxifloxacin 400mg once daily Days 1-56; plus PA-824 200mg once daily Days 1-56; plus pyrazinamide 1500mg once daily Days 1-56.
Drug: Pa-824
oral
Drug: bedaquiline
oral
Other Names:
  • TMC207
  • Sirturo
Drug: moxifloxacin
oral
Other Names:
  • BAY 12-8039
  • Avelox
  • Avalon
  • Avelon
Drug: pyrazinamide
oral
Active Comparator: DS-TB: HRZE
Subjects with DS-TB. HRZE tablets (Isoniazid 75mg plus rifampicin 150mg plus pyrazinamide 400mg plus ethambutol 275mg combination tablets) dosed once daily Days 1-56 per the Subject's weight as follows: 30-37kg: 2 tablets; 38-54kg: 3 tablets; 55-70kg: 4 tablets; 71kg and over: 5 tablets.
Drug: isoniazid, rifampicin, pyrazinamide and ethambutol combination tablet
oral

Detailed Description:

The trial design is a phase 2, multi-center, open-label, partially randomized clinical trial in four parallel treatment groups. Subjects with drug-sensitive tuberculosis (DS-TB) will be randomized to receive either J(loading dose/three times a week)PaZ; or J(200mg)PaZ; or HRZE. Subjects with multi drug-resistant tuberculosis will receive J(200mg)MPaZ. The HRZE treatment arm is included as a control for the drug-sensitive treatments and as a control for the quantitative laboratory mycobacteriology testing.

A total of approximately 240 male and female, newly diagnosed subjects with drug-sensitive or multi drug-resistant, smear positive pulmonary tuberculosis aged 18 to 75 years (inclusive) will be included in the study. A total of 180 subjects with drug-sensitive tuberculosis (60 per treatment arm) will be randomized. Up to 60 subjects with multi-drug resistant tuberculosis will be assigned.

All subjects will have up to a maximum of 9 days screening, receive 8 weeks of treatment, and have follow-up visits at 2 and 12 weeks after study treatment completion or last dose of investigational medicinal product in the case of early withdrawal. Subjects who withdraw from the study after receiving < 14 days of investigational medicinal product, will only attend a follow-up visit at 2 weeks after last dose of investigational medicinal product.

Upon treatment completion, the subjects with drug-sensitive tuberculosis will be provided with sufficient doses of standard of care tuberculosis treatment, as appropriate, to cover the time period from attending their last visit at the study clinic until their scheduled visit at the TB clinic. All subjects with drug sensitive and multi-drug resistant tuberculosis will be referred to the local community tuberculosis clinics for standard anti-tuberculosis chemotherapy according to National Tuberculosis Guidelines.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Provide written, informed consent prior to all trial-related procedures. Male or female, aged between 18 and 75 years inclusive.
  2. Body weight (in light clothing and with no shoes) between 35 and 100 kg, inclusive.
  3. Tested at the trial appointed laboratory: M. Tb positive on molecular test (e.g. GeneXpert or Hain) and sputum smear-positive pulmonary TB on direct microscopy for acid-fast bacilli (at least 1+ on the IUATLD/WHO scale.

    • For DS-TB treatment arms (defined as sensitive to rifampicin based on molecular sensitivity testing), Subjects should be:

      1. either newly diagnosed or untreated for at least 3 years after cure from a previous episode (Subject can give a history of cure and previous treatment); AND
      2. Previous TB treatment must be discontinued as per exclusion criteria 16.
    • For MDR-TB treatment arm (defined as resistant to rifampicin based on molecular sensitivity testing), Subjects should be:

      1. sensitive to moxifloxacin by molecular sensitivity testing; AND
      2. either newly diagnosed or could have previously been treated for DS-TB and/or MDR-TB (< 7 days of treatment). Previous MDR-TB treatment must be discontinued as per exclusion criteria 17.
  4. A chest X-ray picture which in the opinion of the Investigator is compatible with TB.
  5. Ability to produce an adequate volume of sputum as estimated from a screening Coached Spot Sputum Sample assessment (estimated 10 ml or more overnight production).
  6. Be of non-childbearing potential or using effective methods of birth control, as defined below:

Non-childbearing potential:

  1. Subject - not heterosexually active or practices sexual abstinence; or
  2. Female Subject/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
  3. Male Subject/sexual partner - vasectomised or has had a bilateral orchidectomy minimally three months prior to screening.

Effective birth control methods:

A double contraceptive method should be used as follows:

  1. Double barrier method which can include any 2 of the following: a male condom, diaphragm, cervical cap, or female condom (male and female condoms should not be used together); or
  2. Barrier method (one of the above) combined with hormone-based contraceptives or an intra-uterine device for the female Subject/partner; and are willing to continue practicing birth control methods throughout treatment and for 6 months (both male and female Subjects) 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 Subjects or female partners of male Subjects to prevent pregnancy).

Exclusion Criteria:

Medical 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. A rapid test for malaria may be carried out if indicated.
  2. Karnofsky performance status score of < 60%.
  3. Poor general condition where any delay in treatment cannot be tolerated per discretion of the Investigator.
  4. Clinically significant evidence of extrathoracic TB (e.g. miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis), as judged by the Investigator.
  5. History of allergy or hypersensitivity to any of the study Investigational Medicinal Products or related substances.
  6. Known or suspected current alcohol and/or drug abuse (positive urine drug screen) or history thereof within the past 2 years that is, in the opinion of the Investigator, sufficient to compromise the safety and/or cooperation of the Subject.
  7. For HIV infected Subjects:

    1. having a CD4+ count <100 cells/µL;
    2. with an AIDS-defining opportunistic infection or malignancies (except pulmonary TB);
    3. currently treated with or will need to initiate antiretroviral therapy (ART) which is not compatible with the allowed ARTs and is not considered an appropriate candidate for switching to a regimen of ARVs which is allowed as follows:

      • Triple nucleoside reverse transcriptase inhibitor (NRTI) based regimen consisting of zidovudine, lamivudine, and abacavir;
      • Nevirapine based regimen consisting of nevirapine in combination with any NRTIs;
      • Lopinavir/ritonavir (Aluvia™) based regimen consisting of lopinavir/ritonavir (Aluvia™) in combination with any NRTIs;
      • Raltegravir in combination with nucleoside reverse transcriptase inhibitors (NRTIs);
    4. cannot ensure a 2 week interval between commencing IMP and the start of ART.
  8. Having participated in other clinical study/ies with investigational agent/s within 8 weeks prior to trial start.
  9. Significant cardiac arrhythmia requiring medication.
  10. Subjects with the following at screening (per measurements and reading done by Central ECG):

    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 are known to prolong the QT/QTc interval (see exclusion criteria 19);
    4. Any clinically significant, in the opinion of the Investigator, ECG abnormality.
  11. Females who are pregnant, breast-feeding, or planning to conceive a child during the study or within 6 months of cessation of treatment. Males planning to conceive a child during the study or within 6 months of cessation of treatment.
  12. Diabetes Mellitus resulting in hospitalization in the past year.
  13. Evidence of lens opacity on slit lamp ophthalmologic examination as defined by a grading of >1+ on the AREDS2 grading system.
  14. For males, any history of a clinically significant abnormality in the reproductive system.

    Specific Treatments

  15. Previously received treatment with PA-824, bedaquiline or moxifloxacin as part of a clinical trial.
  16. For the DS-TB treatment arms: treatment with any drug active against M. Tb within the 3 years prior to Day 1 (including but not limited to isoniazid, ethambutol, amikacin, bedaquiline, clofazimine, cycloserine, fluoroquinolones, rifabutin, rifampicin, streptomycin, kanamycin, para-aminosalicylic acid, rifapentine, pyrazinamide, thioacetazone, capreomycin, thioamides, metronidazole). Exceptions include the use of fluoroquinolones and metronidazole as short-term treatment (≤2 weeks) for Non-M.Tb infections. Treatment should have been discontinued at least 3 months prior to Day 1. 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.
  17. MDR-TB Subjects may have previously been treated for DS-TB with first-line TB drugs (isoniazid, rifampicin, ethambutol, pyrazinamide and/or streptomycin) and/or received ≤7 days MDR-TB treatment, provided that treatment is/was discontinued at least 7 days prior to randomization. It should be confirmed that the MDR-TB treatment can be safely stopped and the screening period is long enough to allow for a washout period of 5 times the longest half-life of the drugs.
  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 acute gout, allergy to any TB drug, their component or to the IMP.
  19. Use of any drug within 30 days prior to dosing known to prolong QTc interval (including but not limited to amiodarone, bepridil, chloroquine, chlorpromazine, cisapride, cyclobenzaprine, clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine). Exceptions may be made for Subjects 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. Subjects who have taken drugs with long elimination half-lives such as amiodarone should be discussed with the Sponsor.
  20. Use of any drugs or substances within 30 days prior to dosing known to be strong inhibitors or inducers of cytochrome P450 enzymes (including but not limited to quinidine, tyramine, ketoconazole, fluconazole, testosterone, quinine, gestodene, metyrapone, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, erythromycin, cocaine, furafylline, cimetidine, dextromethorphan). Exceptions may be made for Subjects 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. Any ARVs other than allowable ARVs detailed in exclusion criteria no. 7 above.

    Based on Laboratory Abnormalities:

  22. Subjects with the following toxicities at screening as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table:

    1. serum magnesium and calcium (corrected for albumin) levels outside of the laboratory's reference range
    2. lipase grade 3 or greater (>2.0 x ULN);
    3. creatinine grade 2 or greater (>1.5 x ULN);
    4. hemoglobin grade 4 (<6.5 g/dL);
    5. platelets > grade 2 (under 50x10(9) cells/L);
    6. serum potassium less than the lower limit of normal for the laboratory;
    7. aspartate aminotransferase (AST) grade 3 or greater (≥3.0 x ULN) to be excluded;
    8. alanine aminotransferase (ALT) grade 3 or greater (≥3.0 x ULN) to be excluded;
    9. 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;
    10. 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 and approved by the Sponsor Medical Monitor
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02193776


Locations
South Africa
The Aurum Institute: Tembisa Hospital
Tembisa, Gauteng, South Africa, 1632
Klerksdorp Tshepong Hospital
Jouberton, Klerksdorp, South Africa, 2570
TASK Applied Science
Cape Town, South Africa, 7531
University of Cape Town Lung Institute (Pty) Ltd
Cape Town, South Africa, 7937
THINK: Tuberculosis & HIV Investigative Network of KwaZulu-Natal
Durban, South Africa
CHRU Themba Lethu Clinic
Johannesburg, South Africa
University of Witwatersrand, Clinical HIV Research Unit (CHRU), Helen Joseph Hospital
Johannesburg, South Africa
Tanzania
Ifakara Health Institute
Bagamoyo, Tanzania
NIMR-Mbeya Medical Research Centre (MMRC)
Mbeya, Tanzania
Uganda
Uganda Case Western Reserve University Research Collaboration
Kampala, Uganda
Sponsors and Collaborators
Global Alliance for TB Drug Development
Investigators
Principal Investigator: Rodney Dawson University of Cape Town Lung Institute
  More Information

Responsible Party: Global Alliance for TB Drug Development
ClinicalTrials.gov Identifier: NCT02193776     History of Changes
Other Study ID Numbers: NC-005-(J-M-Pa-Z)
First Submitted: July 16, 2014
First Posted: July 18, 2014
Last Update Posted: June 30, 2016
Last Verified: June 2016

Keywords provided by Global Alliance for TB Drug Development:
Bedaquiline
Tuberculosis
Multi Drug-Resistant Tuberculosis
Drug-Sensitive Tuberculosis
Pa-824
Moxifloxacin
Pyrazinamide
Nitroimidazole
Quinolone
Pretomanid
NC-005

Additional relevant MeSH terms:
Bedaquiline
Tuberculosis
Hypersensitivity
Tuberculosis, Pulmonary
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Immune System Diseases
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Moxifloxacin
Fluoroquinolones
Rifampin
Isoniazid
Pyrazinamide
Ethambutol
Diarylquinolines
Norgestimate, ethinyl estradiol drug combination
Anti-Bacterial Agents
Anti-Infective Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Contraceptives, Oral, Combined
Contraceptives, Oral
Contraceptive Agents, Female