Various Doses and Durations of Linezolid Plus Bedaquiline & Pretomanid in Participants With Drug Resistant Tuberculosis

A phase 3, multi-center, partially-blinded, randomized clinical trial in 4 parallel treatment groups. Bedaquiline and pretomanid treatment will not be blinded. Linezolid treatment dose and duration will be double-blinded.

Participants will have a screening period of up to 14 days and will be randomized to receive one of the 4 active treatment arms. Participants will be randomized to one of the 4 regimens in a 1:1:1:1 ratio, using an interactive voice and web response system (IXRS) which will utilize a randomization system using stratification with a random element to allocate participants evenly across the arms by HIV status and type of TB.

Each participant will receive 26 weeks of treatment. If participant's week 16 sputum sample is culture positive between the week 16 and week 26 treatment visits and their clinical condition suggests they may have an ongoing TB infection, Investigator may consider extending current treatment to 39 weeks. If the culture results between week 16 and week 26 are contaminated, missing or considered an isolated positive without clinical significance, available culture results should be used to make this decision. All decisions regarding treatment extension should be discussed with and approved by, in consultation with the Sponsor Medical Monitor before implementation. The treatment may also require modification due to toxicities. All dose modifications should be discussed with the Sponsor Medical Monitor prior to implementation, unless a pause or dose reduction is required urgently for safety concerns.

Participants will be followed for 78 weeks after end of treatment.

• Pretomanid (Drug), also known as PA-824, Pa: 200mg tablets
• Linezolid (Drug), also known as L, Lin, Zyvox: Scored 600mg tablets
• Bedaquiline (Drug), also known as TMC-207, B, Sirturo: 100mg tablets
• Placebo Linezolid (Drug): Scored 600 mg tablets

Primary outcomes

• Incidence of Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) Through Follow up Until 26 Weeks After the End of Treatment [26 weeks]: Unfavourable status: 1. Participants not classified as having achieved or maintained culture negative status when last seen 2. Participants previously classified as having culture negative status who, following the end of treatment, have two positive cultures without an intervening negative culture 3. Participants who had a positive culture not followed by at least two negative cultures when last seen 4. Participants dying from any cause during treatment, except from violent or accidental cause, not including suicide 5. Participants definitely or possibly dying from TB related cause during the follow-up phase 6. Participants requiring an extension of their treatment beyond that permitted by the protocol a restart or a change of treatment for any reason except reinfection or pregnancy 7. Participants who have had surgery and the resected tissue is cultured and is positive for MTB 8. Participants lost to follow up or withdrawn from the study before the end of treatment

Secondary outcomes

• Incidence of Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) Through Follow up Until 78 Weeks After the End of Treatment. [78 weeks]: Unfavourable status: 1. Participants not classified as having achieved or maintained culture negative status when last seen 2. Participants previously classified as having culture negative status who, following the end of treatment, have two positive cultures without an intervening negative culture 3. Participants who had a positive culture not followed by at least two negative cultures when last seen 4. Participants dying from any cause during treatment, except from violent or accidental cause, not including suicide 5. Participants definitely or possibly dying from TB related cause during the follow-up phase 6. Participants requiring an extension of their treatment beyond that permitted by the protocol a restart or a change of treatment for any reason except reinfection or pregnancy 7. Participants who have had surgery and the resected tissue is cultured and is positive for MTB 8. Participants lost to follow up or withdrawn from the study before the end of treatment
• Time to Sputum Culture Conversion to Negative Status Through the Treatment Period [26 weeks]: Culture conversion is a diagnostic criteria indicating the point at which samples taken from a patient infected with tuberculosis can no longer produce tuberculosis cell cultures. 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.
• Sputum Culture Conversion to Negative Status at End of Treatment for Those Positive at Baseline [End of Treatment, 26 weeks]: Culture conversion is a diagnostic criteria indicating the point at which samples taken from a patient infected with tuberculosis can no longer produce tuberculosis cell cultures.

Sex: All, ages: 14 Years to any

Inclusion Criteria:

* Male or female, aged 14 years or older.
* One of the following with documentation of culture positive or molecular test within 3 months of screening:

  * XDR-TB defined as resistance to rifamycins, a fluoroquinolone AND an injectable OR
  * Pre-XDR-TB with defined as resistance to rifamycins, and to a fluoroquinolone OR an injectable OR
  * MDR-TB with resistance to rifamycins, and either non-responsive or non-tolerant to current treatment.
* Of non-childbearing potential or willing to practice effective birth control methods.
* Complete informed consent form.

Exclusion criteria:

* Karnofsky score < 60 at screening.
* Body mass index (BMI) < 17 kg/m2
* Participants who are expected to require a surgical procedure (for Pulmonary TB).
* Any risk factor for QT prolongation
* Pregnant or breast-feeding
* Any planned contraindicated medicines or received more than 2 weeks of bedaquiline, linezolid or delamanid prior to first dose of IMP.
* A peripheral neuropathy of Grade 3 or 4, according to DMID. Or, participants 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
* Any of the following lab toxicities/abnormalities:

  * Viral load >1000 copies/mL (Unless newly diagnosed HIV and not yet on ART who otherwise qualify for participation);
  * CD4+ count < 100 cells/µL (HIV positive participants);
  * Serum potassium less than the lower limit of normal for the laboratory;
  * Hemoglobin < 9.0 g/dL or 90g/L;
  * Platelets <100,000/mm3 or < 100 x 10\^9/L
  * Absolute neutrophil count (ANC) < 1500/ mm3 or < 1.5 x 10\^9/L
  * Aspartate aminotransferase (AST) and Alanini aminotransferase (ALT) Grade 3 or greater (> 3.0 x ULN)
  * Total bilirubin greater than 1.5 x ULN
  * Direct bilirubin greater than ULN
  * Serum creatinine level greater than 1.5 times upper limit of normal
  * Albumin <3.0 g/dl or < 30 g/L

Participant flow

Outcome results

• Incidence of Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) Through Follow up Until 26 Weeks After the End of Treatment (Primary), Count of participants, Participants: 1200mg L x 26 Weeks + Pa + B 41; 1200 mg L x 9 Weeks + Pa + B 40; 600 mg L x 26 Weeks + Pa + B 41; 600 mg L x 9 Weeks + Pa + B 37; Total 159
• Incidence of Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) Through Follow up Until 78 Weeks After the End of Treatment. (Secondary), Count of participants, Participants: 1200mg L x 26 Weeks + Pa + B 40; 1200 mg L x 9 Weeks + Pa + B 39; 600 mg L x 26 Weeks + Pa + B 40; 600 mg L x 9 Weeks + Pa + B 35; Total 154
• Time to Sputum Culture Conversion to Negative Status Through the Treatment Period (Secondary), Median, weeks: 1200mg L x 26 Weeks + Pa + B 4 (2 to 8); 1200 mg L x 9 Weeks + Pa + B 4 (2 to 8); 600 mg L x 26 Weeks + Pa + B 6 (3 to 6); 600 mg L x 9 Weeks + Pa + B 6 (3 to 10); Total 6 (3 to 8)
• Sputum Culture Conversion to Negative Status at End of Treatment for Those Positive at Baseline (Secondary), Count of participants, Participants: 1200mg L x 26 Weeks + Pa + B 29; 1200 mg L x 9 Weeks + Pa + B 28; 600 mg L x 26 Weeks + Pa + B 31; 600 mg L x 9 Weeks + Pa + B 31; Total 119

Adverse events

Time frame: 28 weeks

Serious adverse events by term

Other adverse events by term

Limitations and caveats: None reported.

• Results publication: Bruning-Barry R, Ambroso JL, Yang X, Hickman D, Harkins AM, Noble M, Paris M, Foraida S, Sun E, Beumont M. Safety evaluation of pretomanid, an anti-tuberculosis drug, for the treatment of pregnant and lactating women. Antimicrob Agents Chemother. 2026 Aug 5;70(8):e0034326. doi: 10.1128/aac.00343-26. Epub 2026 Jul 10. PMID 42429813
• Results publication: Conradie F, Bagdasaryan TR, Borisov S, Howell P, Mikiashvili L, Ngubane N, Samoilova A, Skornykova S, Tudor E, Variava E, Yablonskiy P, Everitt D, Wills GH, Sun E, Olugbosi M, Egizi E, Li M, Holsta A, Timm J, Bateson A, Crook AM, Fabiane SM, Hunt R, McHugh TD, Tweed CD, Foraida S, Mendel CM, Spigelman M; ZeNix Trial Team. Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis. N Engl J Med. 2022 Sep 1;387(9):810-823. doi: 10.1056/NEJMoa2119430. PMID 36053506

• Study Protocol (PDF, 2020-03-18)
• Statistical Analysis Plan (PDF, 2021-01-29)
• Informed Consent Form (PDF, 2018-06-13)

• Francesca Conradie, Principal investigator, Isango Lethemba TB Research Unit