A randomized controlled trial of two adjunctive host-directed therapies in rifampin-resistant tuberculosis (DRTB-HDT).

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• Any condition for which participation in the trial, as judged by the investigator, could compromise the subject's well-being or prevent, limit, or confound protocol-specified assessments 2. Current or imminent treatment (within 24 hours) for malaria. 3. Pregnancy or breastfeeding 4. Severely ill, such that, in the opinion of the investigator, death is likely during the trial. 5. TB meningitis or other forms of severe TB with increased risk of poor outcome as judged by the investigator. 6. History of allergy or hypersensitivity to any of the study therapies or related substances. 7. Have participated in other clinical trials with investigational agents within 8 weeks prior to study initiation or currently enrolled in an investigational trial. 8. Previous RIF‐R‐TB treatment within the past 12 months 9. Cardiac arrhythmia requiring medication or any clinically significant ECG abnormality, in the opinion of the investigator 10. Requires treatment with drugs that are strong inducers or inhibitors of CYP3A4 (e.g., ketoconazole, lopinavir, or cobicistat), carbonic anhydrase inhibitors (e.g., acetazolamide), or OCT2 or MATE inhibitors (e.g., cimetidine, pyrimethamine). 11. Use of systemic corticosteroids within the past 28 days. 12. History of unstable diabetes mellitus requiring hospitalization for hyper‐ or hypoglycemia within the past year prior to screening or requiring treatment with metformin. 13. Subjects with any of the following abnormal laboratory values: A. creatinine >2 mg/dl b. hemoglobin <8 g/dL/ . c. platelets <100x109 cells/L d. serum potassium <3.5 e. alanine aminotransferase (ALT) ≥2.0 x ULN f. alkaline phosphatase (AP) >5.0 x ULN g. total bilirubin >1.5 mg/dL h. Hepatitis B surface antigen positive i. random blood glucose >140 mg/dL (7.8 mmol/L) j. SARS-CoV-2 PCR or antigen test positive NB: All inclusion criteria and none of the exclusion criteria must be met. NB: Enrolled patients whose initial sputum cultures subsequently fail to demonstrate RIF-R-TB growth will be excluded from the mITT and PP populations. They may be excluded from further study participation based on the individual benefit-risk ratio, as assessed by the study site, PI and DMC.

• Between the ages of 16 and 65 2. Able and willing to provide signed written consent, or verbal consent of witnesses in case of illiteracy, before undertaking any process-related procedures. In the case of children aged 16 or 17 years, consent of at least one parent or guardian plus consent of the child will be required. 3. Body weight (in light clothing without shoes) between 30 and 90 kg. 4. Positive sputum Xpert (TB/RIF or Ultra) with Ct ≤22, with subsequent culture confirmation. 5. RIF resistance diagnosed by Xpert OR Hain test OR phenotypic drug susceptibility testing 6. Chest radiograph meeting National TB Association criteria for moderate or very advanced pulmonary tuberculosis 7. If sexually active, willing to use an effective contraceptive method during TB treatment 8. HIV-1 seronegative, OR if HIV-1 seropositive, presenting to an African study site with a CD4 T-cell count > 100/μl and either currently receiving ART or willing to start ART during study participation, as specified NB: HIV+ patients will only be enrolled in African sites