We're building a better ClinicalTrials.gov. Check it out and tell us what you think!
Try the New Site
We're building a modernized ClinicalTrials.gov! Visit Beta.ClinicalTrials.gov to try the new functionality.
ClinicalTrials.gov Menu

A Phase 3 Study Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus Linezolid in Subjects With Drug Resistant Pulmonary Tuberculosis

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.
ClinicalTrials.gov Identifier: NCT02333799
Recruitment Status : Completed
First Posted : January 7, 2015
Last Update Posted : November 23, 2020
Information provided by (Responsible Party):
Global Alliance for TB Drug Development

Brief Summary:
The purpose of this study is to evaluate the efficacy, safety, tolerability and pharmacokinetics of bedaquiline plus PA-824 plus linezolid after 6 months of treatment (option for 9 months for subjects who remain culture positive at month 4) in Subjects with either pulmonary extensively drug resistant tuberculosis (XDR-TB), treatment intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB).

Condition or disease Intervention/treatment Phase
Pulmonary Tuberculosis Drug: Bedaquiline Drug: PA-824 Drug: Linezolid Phase 3

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 109 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 3 Open-label Trial Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus Linezolid in Subjects With Pulmonary Infection of Either Extensively Drug-resistant Tuberculosis (XDR-TB) or Treatment Intolerant / Non-responsive Multi-drug Resistant Tuberculosis (MDR-TB).
Study Start Date : March 2015
Actual Primary Completion Date : January 14, 2019
Actual Study Completion Date : August 3, 2020

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Bedaquiline + PA-824 + Linezolid
bedaquiline 400 mg once daily for 2 weeks then 200mg 3 times per week plus PA-824 200mg once daily plus linezolid 1200mg once daily .
Drug: Bedaquiline
100mg tablets
Other Names:
  • B
  • TMC-207

Drug: PA-824
200mg tablets
Other Names:
  • Pa
  • pretomanid

Drug: Linezolid
Scored 600mg tablets
Other Names:
  • L
  • Lin

Primary Outcome Measures :
  1. Incidence of bacteriologic failure or relapse or clinical failure through follow up until 6 months after the end of treatment. [ Time Frame: Treatment Period: Day 1, Week 1, 2, 4, 6, 8, 12, 16, 20, 26, 30, 34, 39 Follow Up: Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24 ]

    Bacteriologic failure: During the treatment period, failure to attain culture conversion to negative.

    Bacteriologic relapse: During the follow-up period, failure to maintain culture conversion to negative status in culture, with culture conversion to positive status with a Mycobacterium tuberculosis (M.tb.) strain that is genetically identical to the infecting strain at baseline.

    Clinical failure: A change from protocol-specified TB treatment due to treatment failure, retreatment for TB during follow up, or TB-related death.


    Culture conversion requires at least 2 consecutive culture negative/positive samples at least 7 days apart.

    Subjects who are documented at a visit as unable to produce sputum and who are clinically considered to be responding well to treatment will be considered to be culture negative at that visit.

Secondary Outcome Measures :
  1. Time to sputum culture conversion to negative status through the treatment period. [ Time Frame: Day 1, Week 1, 2, 4, 6, 8, 12, 16, 20, 26, Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24 ]
  2. Proportion of subjects with sputum culture conversion to negative status at 4, 6, 8, 12, 16 and 26 or 39 weeks. [ Time Frame: Week 4, 6, 8, 12, 16, 26, 39 ]
  3. Incidence of Treatment Emergent Adverse Events (TEAEs) presented by incidence, and seriousness, leading to TB related or non-TB related death. [ Time Frame: Day 1, Week 1, 2, 4, 6, 8, 12, 16, 20, 26, 30, 34, 39, Follow-up Month 3, 6, 9, 12, 15, 18, 21, 24 ]
  4. All Subjects- Pre-dose sampling at weeks 2, 8 and 16 to measure Ctrough levels of bedaquiline, bedaquiline metabolite M2, Linezolid and PA-824. [ Time Frame: Weeks 2, 8 and 16 ]
  5. Time to sputum culture positivity [ Time Frame: Treatment Period: Day 1, Week 1, 2, 4, 6, 8, 12, 16, 20, 26, 30, 34, 39 Follow Up: Month 1, 2, 3, 6, 9, 12, 15, 18, 21, 24 ]
    If liquid culture in the MGIT platform is used, the rate of change in time to sputum culture positivity (TTP) over time in the Mycobacterial Growth Indicator Tube (MGIT) system in sputum, represented by the model-fitted log(TTP) results as calculated by the regression of the observed log(TTP) results over time.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Layout table for eligibility information
Ages Eligible for Study:   14 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria

  1. Provide written, informed consent prior to all trial-related procedures (if under 18, include consent of legal guardian).
  2. Body weight of ≥35 kg (in light clothing and no shoes).
  3. Willingness and ability to attend scheduled follow-up visits and undergo study assessments
  4. Provide consent to HIV testing (if an HIV test was performed within 1 month prior to trial start, it should not be repeated as long as documentation can be provided [ELISA and/or Western Blot]. If HIV status is a confirmed known positive, repeated HIV test is not needed provided documentation is available.
  5. Male or female, aged 14 years or above.
  6. Subjects with one of the following pulmonary TB conditions:

    a. XDR-TB with

    i. documented culture positive (for M.tb.) results within 3 months prior to screening or M.tb. confirmed in sputum based on molecular test within 3 months prior to or at screening;

    ii. documented resistance to isoniazid, rifamycins, a fluoroquinolone and an injectable historically at any time or at screening;

    b. MDR-TB documented by culture positive results (for M.tb.) within 3 months prior to or at screening with documented non-response to treatment with the best available regimen for 6 months or more prior to enrolment who in the opinion of the Investigator have been adherent to treatment and will be adherent to study regimen;

    c. MDR-TB documented by culture positive (for M.tb.) results within 3 months prior to or at screening who are unable to continue second line drug regimen due to a documented intolerance to:

    i. PAS, ethionamide, aminoglycosides or fluoroquinolones;

    ii. Current treatment not listed above that renders subject eligible for the study in the Investigator's opinion.

  7. Chest X-Ray picture (taken within a year prior to screening) consistent with pulmonary TB in the opinion of the Investigator.
  8. 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;
  3. 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 investigational medicinal products; therefore, hormone based contraceptives alone cannot be used by female Subjects or female partners of male Subjects to prevent pregnancy.

Exclusion Criteria Medical History

  1. Any condition in the Investigator's opinion (i.e., an unstable disease such as uncontrolled diabetes or cardiomyopathy, extra-pulmonary TB requiring extended treatment), where participation in the trial would compromise the well-being of Subject or prevent, limit or confound protocol specified assessments.
  2. Abuse of alcohol or illegal drugs, that in the opinion of the Investigator would compromise the Subjects' safety or ability to follow through with all protocol-specified visits and evaluations.
  3. In the judgment of the Investigator, the patient is not expected to survive for more than 12 weeks.
  4. Karnofsky score < 50 within 30 days prior to entry.
  5. Body Mass index (BMI) < 17 kg/m²
  6. History of allergy or known hypersensitivity to any of the trial Investigational Medicinal Products or related substances.
  7. HIV infected Subjects having a CD4+ count ≤ 50 cells/μL; For HIV infected Subjects having a CD4+ count >50 cells/μL;

    a. 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. Examples of allowed treatment include but are not limited to the following. If there are any questions, discuss with the Sponsor Medical Monitor for confirmation of appropriate ARV regimen.

    i. Nevirapine based regimen consisting of nevirapine in combination with any NRTIs;

    ii. Lopinavir/ritonavir (Aluvia™) based regimen consisting of lopinavir/ritonavir (Aluvia™) in combination with any NRTIs;

    iii. The combination of tenofovir/lamivudine/abacavir should be considered in patients with normal renal function to address myelosuppression cross toxicity of idovudine and linezolid;

    iv. An alternate regimen that may be considered if the above are not appropriate is a triple nucleosidase reverse transcriptase inhibitors (NRTI) based regimen consisting of zidovudine, lamivudine and abacavir may be used with caution. Regimens including zidovudine should be used with special caution as zivovudine and linezolid may both cause peripheral nerve toxicity;

    v. Raltegravir in combination with nucleoside reverse transcriptase inhibitors (NRTIs). b. Cannot ensure a 2 week interval between commencing IMP and the start of ART, if not already on ARTs.

  8. Having participated in other clinical studies with dosing of investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational study that includes treatment with medicinal agents. Subjects who are participating in observational studies or who are in a follow up period of a trial that included drug therapy may be considered for inclusion.
  9. Significant cardiac arrhythmia requiring medication.
  10. Subjects with the following at Screening:

    1. QTcF interval on ECG >500 msec. Subjects with QTcF > 450 must be discussed with the sponsor medical monitor before enrolment.
    2. History of additional risk factors for Torsade de Pointes, (e.g., heart failure, hypokalemia, family history of Long QT Syndrome);
    3. Clinically significant ventricular arrhythmias;
    4. Subjects with other cardiac abnormalities that may place them at risk of arrhythmias must be discussed with the sponsor medical monitor before enrolment. Such abnormalities include: Evidence of ventricular pre-excitation (e.g., Wolff Parkinson White syndrome); Electrocardiographic evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; Evidence of second or third degree heart block; Intraventricular conduction delay with QRS duration more than 120 msec.
  11. Females who have a positive pregnancy test at Screening or already known to be pregnant, breastfeeding, 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. A peripheral neuropathy of Grade 3 or 4, according to DMID (Appendix 2). Or, subjects with a Grade 1 or 2 neuropathy which is likely to progress/worsen over the course of the study, in the opinion of the Investigator.
  13. Concomitant use of Monoamine Oxidase Inhibitors (MAOIs) or prior use within 2 weeks of treatment assignment.
  14. Concomitant use of serotonergic antidepressants or prior use within 3 days of treatment assignment if Investigator foresees potential risks for serotonin syndrome when combined with linezolid.
  15. Concomitant use of any drug known to prolong QTc interval (including, but not limited to, amiodarone, bepridil, chloroquine, chlorpromazine, cisapride, cyclobenzaprine, clarithromycin, disopyramide, dofetilide, domperidone, droperidol, erythromycin, fluoroquinolones, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine).
  16. Concomitant use of any drug known to induce myelosuppression.
  17. 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.
  18. Subjects may have previously been treated for DS/MDR-TB (with specific excepetions for Bedaquiline and/or linezolid as noted below) provided that treatment is/was discontinued at least 3 days prior to treatment assignment.
  19. Subjects should not receive more than 2 weeks of bedaquiline or linezolid prior to enrolment/first dose of IMP.

    Based on Laboratory Abnormalities

  20. Subjects with the following toxicities at Screening (labs may be repeated) as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November 2007):

    1. serum potassium less than the lower limit of normal for the laboratory;
    2. Hemoglobin level grade 2 or greater (< 8.0 g/dL);
    3. Platelets grade 2 or greater(<75,000/mm3);
    4. Absolute neutrophil count (ANC) < 1000/ mm3;
    5. Aspartate aminotransferase (AST)

      Grade 3 or greater (> 3.0 x ULN) to be excluded;

      Greater than ULN must be discussed with and approved by the sponsor Medical Monitor

    6. Alanine aminotransferase

      Grade 3 or greater (> 3.0 x ULN) to be excluded

      greater than ULN must be discussed with and approved by the sponsor medical monitor ;

    7. Total bilirubin:

      Grade 3 or greater (≥2.0 x ULN), or if ≥1.5 up to 2.0 x ULN when accompanied by an increase in other liver function test (ALT, AST, Alk Phos or GGT);

      1-1.5 x ULN must be discussed with and approved by the sponsor Medical Monitor

    8. Direct bilirubin:

      Greater than ULN to be excluded

    9. Serum creatinine level greater than 2 times upper limit of normal
    10. Albumin <32 g/L

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): NCT02333799

Layout table for location information
South Africa
Task Applied Science - Brooklyn Chest Hospital
Ysterplaat, Cape Town, South Africa, 7405
King DinuZulu Hospital Complex
Sydenham, Durban, South Africa, 4001
Sizwe Tropical Disease Hospital
Sandringham, Johannesburg, South Africa, 2131
Sponsors and Collaborators
Global Alliance for TB Drug Development
Layout table for investigator information
Principal Investigator: Dan Everitt, MD Global Alliance for TB Drug Development
Principal Investigator: Francesca Conradie, MD CHRU Themba Lethu Clinic - Helen Joseph Hospital
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Global Alliance for TB Drug Development
ClinicalTrials.gov Identifier: NCT02333799    
Other Study ID Numbers: NiX-TB-(B-L-Pa)
First Posted: January 7, 2015    Key Record Dates
Last Update Posted: November 23, 2020
Last Verified: November 2020
Keywords provided by Global Alliance for TB Drug Development:
Multi-drug resistant
Extensively drug resistant
Additional relevant MeSH terms:
Layout table for MeSH terms
Tuberculosis, Pulmonary
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Bacterial Infections and Mycoses
Respiratory Tract Infections
Lung Diseases
Respiratory Tract Diseases
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antitubercular Agents