Program for Rifampicin-Resistant Disease With Stratified Medicine for Tuberculosis

Inclusion Criteria:

An individual must meet all of the following inclusion criteria at the time of enrollment in order to participate in this study:

1. Confirmed fluoroquinolone-susceptible rifampicin-resistant pulmonary tuberculosis,based on sputum Xpert MTB/RIF and Xpert MTB/XDR, and/or other validated moleculartest, and/or phenotypic drug susceptibility testing. a. NOTE: TB diagnosis for purposes of meeting this inclusion criterion can be from astudy testing laboratory or from an outside laboratory.

2. Aged ≥ 14 years.

3. A verifiable address or residence location that is readily available for visiting,willingness to consent to home visits and phone calls, and willingness to inform thestudy team of any change of address during the treatment and follow-up period.

4. Ability and willingness of individual to provide written informed consent or writtenconsent from a parent, guardian, or caregiver and assent of the child participantper local ethics committee guidance.

5. Documentation of negative HIV infection status within 30 days prior to study entryor documentation confirming HIV infection at any time before study entry.

6. For individuals with HIV: CD4+ cell count ≥ 50 cells/mm3 based on testing performedwithin 30 days prior to study entry.

7. For individuals with HIV: Currently being treated with dolutegravir-basedantiretroviral therapy (ART), or plan to initiate dolutegravir-based ART at orbefore study week 8. a. NOTE: Dosing of ART and chemoprophylaxis for opportunistic infections should bereflective of local standard of care based on WHO or national guidelines. Thefollowing antiretrovirals are disallowed given significant drug-drug interactionswith bedaquiline: efavirenz, etravirine, all protease inhibitors, andcobicistat-boosted elvitegravir. The following antiretroviral is disallowed givenrisk of myelosuppression with linezolid: zidovudine.

8. For individuals who are pregnant: at screening, evidence by ultrasound of a viablesingleton pregnancy with an estimated gestational age at enrollment of ≥ 14 weeks asper screening ultrasound.

9. Chest radiograph obtained within 14 days prior to study entry.

Exclusion Criteria:

An individual meeting any of the following exclusion criteria at the time of enrollment or initiation of study drugs will be excluded from study participation:

1. Known allergy/sensitivity, intolerance, or any hypersensitivity to components ofstudy TB drugs or their formulation.

2. One or more of the following laboratory parameters:

3. Absolute neutrophil count (ANC) < 1000/mm3.

4. Hemoglobin level < 8.0 g/dL.

5. Serum or plasma alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 times the upper limit of normal.

6. Serum or plasma total bilirubin ≥ 3 times the upper limit of normal.

7. Serum or plasma creatinine level ≥ 3 times the upper limit of normal.

8. Evidence of laboratory values consistent with or equivalent to grade 4 toxicity (i.e., potentially life-threatening).

9. NOTE: Persons found not to be eligible due to laboratory abnormalities may bereevaluated within the screening window.

10. QTcF interval ≥ 480 ms within 5 days prior to study entry.

11. One or more risk factors for QT prolongation (apart from age and sex) or otheruncorrected risk factors for torsades de pointes: evidence of ventricularpre-excitation (Wolff-Parkinson-White syndrome); electrocardiographic evidence ofeither complete left bundle branch block or right bundle branch block, or incompleteleft bundle branch block or right bundle branch block and QRS complex duration ≥ 120ms on at least one ECG; current pacemaker implant; congestive heart failure;evidence of second- or third-degree heart block; bradycardia defined by sinus rateless than 50 bpm; personal or family history of long QT syndrome; personal historyof arrhythmic cardiac disease, with the exception of sinus arrhythmia; personalhistory of syncope (i.e., cardiac syncope not including syncope due to vasovagal orepileptic causes).

12. Current grade 2 or higher peripheral neuropathy. a. NOTE: Peripheral neuropathy assessment must be obtained within 7 days prior tostudy entry.

13. Documentation of Karnofsky Performance Status Score < 50 obtained within 14 daysprior to study entry.

14. Known resistance to bedaquiline, pretomanid, delamanid, linezolid, orfluoroquinolones.

15. Previous use of any second-line anti-TB drugs for more than 14 days during the 12months prior to the screening visit date.

16. Known or presumed central nervous system TB, osteoarticular TB, ormiliary/disseminated TB in the current TB episode.

17. Taking any medication that is contraindicated with study medicines which cannot bestopped (with or without replacement) or requires a washout period longer than 2weeks.

18. Any condition (social or medical or psychological) which, in the opinion of theinvestigator, would make participation unsafe or interfere with adherence to studyrequirements.

19. Current enrollment in other therapeutic trials will not be eligible. a. NOTE:Current enrollment of index cases in prevention trials will be allowed on acase-by-case basis, provided that the prevention trial does not include atherapeutic intervention that could affect response to TB treatment.

All persons who are not eligible for the PRISM-TB trial will be managed according to local routine practice and may enroll in other studies.

Criteria for Exclusion after Entry ('Late Exclusion'):

Enrolled individuals who are subsequently determined to meet the following criteria will be classified as 'late exclusions' and study treatment will be discontinued:

1. Bedaquiline, pretomanid, delamanid, linezolid, or fluoroquinolone resistance on phenotypic or molecular drug- susceptibility testing from samples collected up to 4 weeks after randomization.