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

NCT02333799 | Completed Phase 3 Results DMC

• 1 other identifier: Nix-TB-(B-L-Pa)
• Study Type: interventional
• Target: 109
• Locations: 1 country
• Sites: 3

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 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).

Conditions

Pulmonary Tuberculosis

Keywords

Tuberculosis; MDR-TB; XDR-TB; Multi-drug resistant; Extensively drug resistant; Bedaquiline; PA-824; Linezolid; TB; Pretomanid; TMC-207; NiX-TB

Outcome Measures

Primary Outcomes (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.

  6 Months post End of Treatment

Secondary Outcomes (6)

• 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.

  24 Months post End of Treatment

• Time to Sputum Culture Conversion to Negative Status Through the Treatment Period

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

• Proportion of Participants With Sputum Culture Conversion to Negative Status

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

• Number of Treatment Emergent Adverse Events (TEAEs)

  Day 1 to 14 days post-End of Treatment

• Incidence of Treatment Emergent Adverse Events (TEAEs) of Special Interest

  Day 1 to 14 days post-End of Treatment

Study Arms (1)

Bedaquiline + PA-824 + Linezolid

EXPERIMENTAL

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. 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.

Drug: Bedaquiline; Drug: PA-824; Drug: Linezolid

Interventions

Bedaquiline DRUG

100mg tablets

Also known as: B, TMC-207

Bedaquiline + PA-824 + Linezolid

PA-824 DRUG

200mg tablets

Also known as: Pa, pretomanid

Bedaquiline + PA-824 + Linezolid

Linezolid DRUG

Scored 600mg tablets

Also known as: L, Lin

Bedaquiline + PA-824 + Linezolid

Eligibility Criteria

• Age: 14 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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):
• a. Extensively Drug Resistant Tuberculosis (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. 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;
• 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.
• \. Chest X-Ray picture (taken within a year prior to screening) consistent with pulmonary TB in the opinion of the Investigator.

You may not qualify if:

• 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
• Significant cardiac arrhythmia requiring medication.
• 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):
• a. 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

Sponsors & Collaborators

• Global Alliance for TB Drug Development: lead

Study Sites (3)

Task Applied Science - Brooklyn Chest Hospital

Ysterplaat, Cape Town, 7405, South Africa

Location

King DinuZulu Hospital Complex

Sydenham, Durban, 4001, South Africa

Location

Sizwe Tropical Disease Hospital

Sandringham, Johannesburg, 2131, South Africa

Location

Related Publications (3)

• 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.

  PMID: 36804834 DERIVED

• 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.

  PMID: 34604901 DERIVED

• 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.

  PMID: 32130813 DERIVED

Related Links

• TB Alliance Website

MeSH Terms

Conditions

Tuberculosis, Pulmonary; Tuberculosis; Tuberculosis, Multidrug-Resistant; Extensively Drug-Resistant Tuberculosis

Interventions

bedaquiline; pretomanid; Linezolid

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Oxazolidinones; Oxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Eugene Sun, MD
• Organization: Global Alliance for TB Drug Development

eugene.sun@tballiance.org

212-227-7540

Study Officials

• Morounfolu Olugbosi, MD

  Global Alliance for TB Drug Development

  PRINCIPAL INVESTIGATOR

• Francesca Conradie, MD

  CHRU Themba Lethu Clinic - Helen Joseph Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 6, 2015
• First Posted: January 7, 2015
• Study Start: March 1, 2015
• Primary Completion: January 14, 2019
• Study Completion: August 3, 2020
• Last Updated: September 8, 2025
• Results First Posted: August 9, 2024

Record last verified: 2025-08

Locations

ZA (3)