Shortened Regimen for Drug-susceptible TB in Children

Inclusion Criteria:

• Parent or guardian is willing and able to provide written informed consent forpotential participant's study participation; in addition, when applicable per EthicsCommittee/Institutional Review Board (EC/IRB) policies and procedures, potentialparticipant is willing and able to provide assent for study participation.

• At Entry, age of less than 10 years.

• At Entry, weight 3 kilograms (kg) or greater.

• At Entry, diagnosed with TB disease, defined as:

• Pulmonary (including pleural effusion) and/or lymph node (extra-thoracic and/orintra-thoracic) TB with or without bacteriologic confirmation;

• Clinician has decided to treat with standard first-line drug-susceptible TBregimen.

• Known HIV status or HIV testing in progress based on meeting testing requirements.

• Has normal, Grade 1 or 2 test results for all of the following done at or within 14days of Entry (including the most recent):

• Alanine aminotransferase (ALT) less than or equal to 5 times the upper limit ofnormal;

• Total bilirubin less than or equal to 2.5 times the upper limit of normal;

• Potassium level of 3.0 milliequivalent/L or greater;

• Hemoglobin level of 7.0 g/dL or greater;

• Platelet count of 100,000/mm3 or greater;

• Estimated glomerular filtration rate (eGFR; bedside Schwartz formula) 60mL/min/1.73m2 or higher.

• For children living with HIV:

• On antiretroviral therapy (ART) at Entry: Must be on, or able to be switched toa dolutegravir-based regimen at or prior to Entry;

• Not on ART at Entry: Planned initiation of dolutegravir before or at study Week

• For participants who have reached menarche or who are engaging in sexual activity (self-reported): negative serum or urine pregnancy test within 7 days of Entry.

• For participants who are engaging in sexual activity that could lead to pregnancy (self-reported): agrees to practice at least one non-hormonal method ofcontraception or abstain from heterosexual intercourse during study drug treatmentand for 30 days after stopping study medications. Non-hormonal methods include:

• Male or female condoms

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

• Non-hormonal intrauterine device (IUD) or intrauterine system (IUS)

• At Entry, intends to remain in the catchment area of the study site for the durationof study follow-up or willingness to be followed up beyond the catchment areaif/when applicable, as determined by the site investigator based onparticipant/parent/guardian report.

Exclusion Criteria:

• Presumed or documented extra-pulmonary TB involving the central nervous systemand/or bones and/or joints, and/or miliary TB, and/or pericardial TB and/or TB ofthe gastrointestinal (GI) tract and/or renal TB.

• Premature infant (born less than 37-weeks gestation) who is less than 3 months ofage at Entry.

• Any known contraindication to taking any study drug:

• Known allergy or intolerance to any of the study drugs or drugs in the sameclass as the study drugs;

• Any prohibited medications within three days prior to Entry or planned usewithin the following 6 months;

• Unable to take oral medications;

• Known history of prolonged QT syndrome not caused by electrolyte derangements.

• Received more than 10 days of treatment directed against TB disease within 6 monthspreceding initiation of study drugs.

• M. tuberculosis isolate known or suspected to be resistant to isoniazid, rifampin,pyrazinamide, ethambutol, and/or fluoroquinolones.

• Known exposure to an infectious adult with drug-resistant TB, including resistanceto isoniazid, rifampin, pyrazinamide, ethambutol, and/or fluoroquinolones.

• Has any other documented or suspected clinically significant medical condition orany other condition that, in the opinion of the site investigator, would makeparticipation in the study unsafe, complicate interpretation of study outcome data,or otherwise interfere with achieving the study objectives.

• Previously enrolled in this study.

Late Exclusions:

• M. tuberculosis cultured or detected through World Health Organization (WHO)approved molecular assays (e.g., Cepheid Xpert MTB/RIF, Xpert XDR, sequencing orHain MTB-DR plus assays) from sputum, swallowed sputum, nasopharyngeal aspirates,stool, or lymph node aspirate obtained around the time of study entry is determinedto be resistant to isoniazid and/or rifampin and/or pyrazinamide and/or ethambutoland/or fluoroquinolones.

• Any child with a clinical TB diagnosis who is found to have a definitive alternativediagnosis for their presenting signs and symptoms whose TB treatment is discontinuedprior to completion.