Trial of Novel Regimens for the Treatment of Pulmonary Tuberculosis

Inclusion Criteria:

1. Pulmonary TB (among individuals either without history of prior TB treatment or withhistory of TB treatment more than 5 years prior to study entry), identified within 7days prior to study entry by at least one sputum specimen positive for Mtb by Xpert.Semiquantitative Mtb results of "medium" or "high" are required.

2. Pulmonary TB with documented INH susceptibility (by Line Probe Assay (LPA) or XpertMTB/XDR or other validated molecular test) and with documented RIF susceptibility (by LPA or Xpert MTB/RIF or Xpert MTB/RIF Ultra or other validated molecular test)within 7 days prior to study entry.

3. Documentation of HIV-1 infection status, as below:

• Presence or Absence of HIV-1 infection, as documented by:

• Any licensed rapid HIV test or HIV-1 enzyme or chemiluminescenceimmunoassay (E/CIA) test kit, any time prior to study entry. AND

• Confirmed by one of the following:

• A second antibody test from different manufacturers or based on differentprinciples and epitopes (combination antigen-antibody-based rapid testsmay be used), or

• HIV-1 antigen, or

• Plasma HIV-1 RNA viral load, or

• A licensed Western blot

4. For individuals with HIV: CD4+ cell count ≥100 cells/mm3 based on testing performedwithin 30 days prior to study entry.

5. For individuals with HIV: Currently being treated with dolutegravir-basedantiretroviral therapy (ART), or plan to initiate dolutegravir-based ART at orbefore study week 8.

6. Individuals age ≥18 years.

7. The following laboratory values obtained within 7 days prior to study entry at anynetwork-approved non-US laboratory that operates in accordance with Good ClinicalLaboratory Practices (GCLP) and participates in appropriate external qualityassurance programs:

• Serum or plasma alanine aminotransferase (ALT) ≤3 times the upper limit ofnormal (ULN)

• Serum or plasma total bilirubin ≤2 times ULN

• Serum or plasma creatinine ≤2 times ULN

• Serum or plasma potassium ≥3.5 mEq/L

• Serum or plasma magnesium ≥1.0 mEq/L (≥0.500 mmol/L)

• Absolute neutrophil count (ANC) ≥1500/mm^3

• Hemoglobin ≥9.5 g/dL for individuals assigned to female sex at birth and ≥10.0g/dL for individuals assigned to male sex at birth

• Platelet count ≥100,000/mm^3

• Negative for hepatitis B core antibody (HBcAb) total, hepatitis B surfaceantigen (HBsAg)

• Negative for hepatitis C virus (HCV) antibody (or if HCV antibody positive,must have a negative HCV PCR)

8. For individuals assigned to female sex at birth and who are of reproductivepotential, negative pregnancy test (urine HCG or serum β-HCG) within 3 days (72hours) prior to entry by any network-approved non-US laboratory or clinic thatoperates in accordance with GCLP and participates in appropriate external qualityassurance programs. Individuals assigned to female sex at birth, who are of reproductive potential, andwho participate in sexual activity that could lead to pregnancy must agree to use atleast two of the following forms of birth control while receiving TB studymedications and for 12 months after stopping study medications:

• Male or female condoms

• Diaphragm or cervical cap (with spermicide, if available)

• Intrauterine device (IUD) or intrauterine system (IUS)

• Hormone-based birth control (e.g., oral contraceptives, Depo-Provera, NuvaRing,implants)

9. For individuals who are assigned male sex at birth who engage in sexual activitythat may lead to pregnancy in their partner must agree to either remain abstinent oruse male contraceptives. They are also strongly advised to inform their non-pregnantsexual partners of reproductive potential to use effective contraceptives while theindividual is on study and for 90 days after experimental treatment discontinuation.

10. For individuals assigned male sex at birth with pregnant partners, willingness touse condoms during vaginal intercourse while on study and for 90 days afterexperimental treatment discontinuation.

11. For individuals assigned male sex at birth, willingness to refrain from spermdonation while on study and for 90 days after experimental treatmentdiscontinuation.

12. Documentation of Karnofsky performance score ≥60 obtained within 14 days prior tostudy entry.

13. Chest x-ray obtained within 14 days prior to study entry.

14. A verifiable address or residence readily accessible for visiting, and willingnessto inform the study team of any change of address during study treatment andfollow-up period.

15. Ability and willingness of individual to provide informed consent.

Exclusion Criteria:

1. More than cumulative 7 days of treatment directed against active TB for the currentTB episode in the 60 days preceding study entry.

2. Current extrapulmonary TB, in the opinion of the investigator.

3. QTcF interval >450 ms within 7 days prior to study entry.

4. History of or ongoing heart failure.

5. Personal or family history of congenital QT prolongation.

6. History of known, untreated, ongoing hypothyroidism.

7. History of or ongoing bradyarrhythmia.

8. History of torsades de pointes.

9. Current Grade 2 or higher peripheral neuropathy.

10. Other medical conditions (e.g., diabetes, liver or kidney disease, blood disorders,chronic diarrhea), in the opinion of the site investigator, in which the currentclinical condition of the participant is likely to prejudice the response to, orassessment of, treatment.

11. Pregnant or breastfeeding or planning to become pregnant within the next 12 months.

12. Weight <35 kg.

13. Unable to take oral medications.

14. Taking any of prohibited medications.

15. Known allergy/sensitivity or any hypersensitivity to components of investigationalagents or their formulation.

16. Active drug or alcohol use or dependence; or mental illness (e.g., major depression)that, in the opinion of the site investigator, would interfere with adherence tostudy requirements.

17. Taking an investigational drug or vaccine within 30 or more days prior to studyentry.