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Pulmonary TuberculosisPhase 3NCT02333799

A Phase 3 Trial Assessing Safety and Efficacy of B-Pa-L in Participants With DR-TB

A Phase 3 study testing Bedaquiline, PA-824 and Linezolid in people with Pulmonary Tuberculosis, run by Global Alliance for TB Drug Development at 3 sites in South Africa.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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 participants who remain culture positive at month 4) in participants with either pulmonary extensively drug resistant… Read more about this study

Who is it for?
Ages 14 years and older
Conditions the study is for
Pulmonary Tuberculosis
What is being tested?
Bedaquiline, PA-824 and Linezolid
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
109 participants
Where
3 sitesSouth Africa
Study dates
Mar 2015to 3 Aug 2020
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 14 years and older
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • Provide written, informed consent prior to all trial-related procedures (if under 18, include consent of legal guardian).
  • Body weight of ≥35 kg (in light clothing and no shoes).
  • Male or female, aged 14 years or above.
  • Subjects with one of the following pulmonary TB conditions (WHO definitions prior to 2021):
  • Extensively Drug Resistant Tuberculosis (XDR-TB) with
  • 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;
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  • documented resistance to isoniazid, rifamycins, a fluoroquinolone and an injectable historically at any time or at screening;
  • Multi-Drug Resistant Tuberculosis (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;
  • 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:
  • PAS, ethionamide, aminoglycosides or fluoroquinolones;
  • Current treatment not listed above that renders subject eligible for the study in the Investigator's opinion.
  • 6. Chest X-Ray picture (taken within a year prior to screening) consistent with pulmonary TB in the opinion of the Investigator.

Who cannot join

  • Karnofsky score < 50 within 30 days prior to entry.
  • Body Mass index (BMI) < 17 kg/m²
  • History of allergy or known hypersensitivity to any of the trial Investigational Medicinal Products or related substances.
  • HIV infected Subjects having a CD4+ count ≤ 50 cells/μL
  • 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.
  • Significant cardiac arrhythmia requiring medication.
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  • Subjects with the following at Screening:
  • QTcF interval on ECG >500 msec.
  • History of additional risk factors for Torsade de Pointes, (e.g., heart failure, hypokalemia, family history of Long QT Syndrome);
  • Clinically significant ventricular arrhythmias;
  • 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.
  • 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.
  • 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.
  • Concomitant use of Monoamine Oxidase Inhibitors (MAOIs) or prior use within 2 weeks of treatment assignment.
  • Subjects with the following toxicities at Screening as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November 2007):
  • serum potassium less than the lower limit of normal for the laboratory; b. Hemoglobin level grade 2 or greater (< 8.0 g/dL); c. Platelets grade 2 or greater(<75,000/mm3); d. Absolute neutrophil count (ANC) < 1000/ mm3; e. Aspartate aminotransferase (AST) > 3 x ULN g. Total bilirubin > or = to 2xULN h. Direct bilirubin > ULN i. Serum creatinine level greater than 2 times upper limit of normal j. Albumin <32 g/L

Trial locations and contacts

3 sites in 1 country.

South Africa3 sites

  • Sizwe Tropical Disease Hospital

    Sandringham, Johannesburg, 2131

  • King DinuZulu Hospital Complex

    Sydenham, Durban, 4001

  • Task Applied Science - Brooklyn Chest Hospital

    Ysterplaat, Cape Town, 7405

Other trials in South Africa

About this study

Official title: A Phase 3 Open-label Trial Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus Linezolid in Participants With Pulmonary Infection of Either XDR-TB or Treatment Intolerant / Non-responsive MDR-TB.

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 participants who remain culture positive at month 4) in participants with either pulmonary extensively drug resistant tuberculosis (XDR-TB), treatment intolerant or non-responsive multi-drug resistant tuberculosis (MDR-TB).

Read the detailed description

Up to 200 male and female participants aged 14 and over with confirmed sputum positive for M.tb. in culture pulmonary XDR-TB, or with pulmonary MDR-TB with a documented intolerability or non-response to the best treatment available for 6 months or more will be enrolled.

All participants will have up to a maximum of 9 days for screening, receive 6 months of treatment, and have followup visits performed 1 and 2 months after treatment completion and every 3 months after study treatment completion for 24 months. If a participant is culture positive or revert to being culture positive between Month 4 and Month 6 visits and their clinical condition suggests they may have ongoing TB infection, they may have treatment extended to 9 months (with 24 months of Follow Up) or be withdrawn from the study.

Participants who withdraw after <14 days of IMP should attend an Early Withdrawal visit. Participants who withdraw after >15 days of IMP should return for an Early Withdrawal visit and follow-up visits at 3, 6 and 24 months after their last dose of IMP to check for survival, SAEs and resolution of TB symptoms.

Being tested
Bedaquiline, PA-824, Linezolid
Keywords
Tuberculosis, MDR-TB, XDR-TB, Multi-drug resistant, Extensively drug resistant, Bedaquiline, PA-824, Linezolid, TB, Pretomanid, TMC-207, NiX-TB
Medical subject headings
Tuberculosis, Pulmonary, Tuberculosis, Tuberculosis, Multidrug-Resistant, Extensively Drug-Resistant Tuberculosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BedaquilineDrug

    Also called B, TMC-207

    100mg tablets

  • PA-824Drug

    Also called Pa, pretomanid

    200mg tablets

  • LinezolidDrug

    Also called L, Lin

    Scored 600mg tablets

Study groups in NCT02333799
Study groupRoleWhat they receive
Bedaquiline + PA-824 + LinezolidExperimentalbedaquiline 400 mg once daily for 2 weeks then 200mg 3 times per week plus PA-824 200mg once daily plus linezolid 1200mg once daily. A reduction in the dose of linezolid (to either 600 mg qd or 300 mg qd), or temporary cessation of linezolid (due to a linezolid-specific toxicity), or of the full regimen per Investigator discretion was allowed for suspected drug related toxicity. Re-introduction of the regimen could be considered post a cessation not greater than 35 consecutive days. If participants had toxicity events related to linezolid prohibiting further treatment with that drug, they could remain on the bedaquiline and pretomanid study IMP if they received the initial total of 1200 mg daily dose of linezolid for at least the first 4 consecutive weeks of treatment and they were smear negative, or with trace/scanty results and judged to be clinically improving by the Investigator.
Receives: Drug: Bedaquiline; Drug: PA-824; Drug: Linezolid

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Proportion of Treatment Failure (Unfavorable Outcome), Defined as Bacteriologic Failure or Relapse or Clinical Failure (Derived) Through Follow-up Until 6 Months After the End of Treatment.

    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 tuberculosis (TB) treatment due to treatment failure, retreatment for TB during follow up, or TB-related death.

    Note:

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

    Participants 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.

    Measured: 6 Months post End of Treatment

Secondary outcomes (6)

  1. Proportion of Treatment Failure (Unfavorable Outcome), Defined as Bacteriologic Failure or Relapse or Clinical Failure (Derived) Through Follow-up Until 24 Months After the End of Treatment.

    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.

    Note:

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

    Participants 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.

    Measured: 24 Months post End of Treatment

  2. Time to Sputum Culture Conversion to Negative Status Through the Treatment Period

    Median time (in weeks) to culture negative status (first of 2 negative cultures without an intervening positive culture), MITT analysis.

    Measured: Day 1 through End of Treatment, approximately 6 to 9 months of treatment

  3. Proportion of Participants With Sputum Culture Conversion to Negative Status

    Proportion of participants with sputum culture conversion to negative status for those positive at baseline at 4, 6, 8, 12, 16, and End of Treatment (26 or 39 weeks)

    Measured: Week 4, 6, 8, 12, 16, 26, 39

  4. Number of Treatment Emergent Adverse Events (TEAEs)

    Treatment-emergent adverse events (TEAEs): adverse events which started or worsened on or after the first trial drug administration up to and including 14 days after the last trial drug administration. Grade I, II, III, IV TEAEs: DMID grade is indicated as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) and Grade 4 (potentially life-threatening). TEAEs of special interest based on Section 7.3 of the protocol. Liver-related adverse events: any adverse event with a High Level Group Term of HEPATIC AND BILIARY NEOPLASMS BENIGN, HEPATIC AND HEPATOBILIARY DISORDERS, HEPATOBILIARY DISORDERS CONGENITAL, HEPATOBILIARY NEOPLASMS MALIGNANT AND UNSPECIFIED, HEPATOBILIARY INVESTIGATIONS or HEPATOBILIARY THERAPEUTIC PROCEDURES.

    Measured: Day 1 to 14 days post-End of Treatment

  5. Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest

    Treatment-emergent adverse events (TEAEs): Defined as adverse events which started or worsened on or after the first trial drug administration up to and including 14 days after the last trial drug administration. TEAEs of special interest: Identified by prespecified SMQ codes as confirmed by TB Alliance.

    Section 7.3 of the protocol specified the "Monitoring and Safety for Specific Toxicities" and are presented here as TEAEs of special interest. These specific toxicities of interest were based on nonclinical toxicology findings of concern for any of the 3 trial drugs, or from identified toxicities based on the IBs for pretomanid and bedaquiline, on the product label for linezolid and literature reports of linezolid long-term toxicity.

    Measured: Day 1 to 14 days post-End of Treatment

  6. Incidence of Nervous System Disorders - Peripheral Neuropathy Events Grouped

    Treatment-emergent adverse events (TEAEs): Defined as adverse events which started or worsened on or after the first trial drug administration up to and including 14 days after the last trial drug administration.

    #: Indicates TEAEs of special interest. TEAEs of special interest: Identified by pre-specified SMQ codes as confirmed by TB Alliance. Adverse events in System Organ Class "NERVOUS SYSTEM DISORDERS" are presented into the table. Preferred term "PERIPHERAL NEUROPATHY" was a grouping of terms "PERIPHERAL SENSORY NEUROPATHY", "NEUROPATHY PERIPHERAL", "PARAESTHESIA", "HYPOAESTHESIA", "PERIPHERAL MOTOR NEUROPATHY", "BURNING SENSATION", "HYPOREFLEXIA" and "PERIPHERAL SENSORIMOTOR NEUROPATHY".

    Measured: Day 1 to 14 days post-End of Treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 Jan 2015 (estimated)
  2. Study startMar 2015
  3. Primary completion14 Jan 2019
  4. Study completion3 Aug 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
109 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02333799
Sponsor's protocol ID
Nix-TB-(B-L-Pa)
Status last verified
Aug 2025
First submitted
6 Jan 2015
Last updated
8 Sep 2025
Data monitoring committee
Yes

Publications

  • Solans BP, Imperial MZ, Olugbosi M, Savic RM. Analysis of Dynamic Efficacy Endpoints of the Nix-TB Trial. Clin Infect Dis. 2023 Jun 8;76(11):1903-1910. doi: 10.1093/cid/ciad051.

    PubMed 36804834

  • Imperial MZ, Nedelman JR, Conradie F, Savic RM. Proposed Linezolid Dosing Strategies to Minimize Adverse Events for Treatment of Extensively Drug-Resistant Tuberculosis. Clin Infect Dis. 2022 May 30;74(10):1736-1747. doi: 10.1093/cid/ciab699.

    PubMed 34604901

  • Conradie F, Diacon AH, Ngubane N, Howell P, Everitt D, Crook AM, Mendel CM, Egizi E, Moreira J, Timm J, McHugh TD, Wills GH, Bateson A, Hunt R, Van Niekerk C, Li M, Olugbosi M, Spigelman M; Nix-TB Trial Team. Treatment of Highly Drug-Resistant Pulmonary Tuberculosis. N Engl J Med. 2020 Mar 5;382(10):893-902. doi: 10.1056/NEJMoa1901814.

    PubMed 32130813

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Bedaquiline, PA-824 and Linezolid in people with Pulmonary Tuberculosis, run by Global Alliance for TB Drug Development at 3 sites in South Africa.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 12 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 8 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 9 Aug 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Proportion of Treatment Failure (Unfavorable Outcome), Defined as Bacteriologic Failure or Relapse or Clinical Failure (Derived) Through Follow-up Until 6 Months After the End of Treatment. (time frame: 6 Months post End of Treatment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02333799, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Sep 2025.

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