Study of a Single Dose of Pretomanid Added to an Optimized Background Regimen in Children With Rifampicin-Resistant Tuberculosis

Inclusion Criteria:

• If not of legal age or circumstance to provide independent informed consent asdetermined by site standard operating procedures (SOPs) and consistent withinstitutional review board/ethics committee (IRB/EC) policies and procedures:Parent/legal guardian is willing and able to provide written informed consent forpotential participant's study participation; in addition, when applicable per IRB/ECpolicies and procedures, potential participant is willing and able to providewritten assent for study participation.

• If of legal age or circumstance to provide independent informed consent asdetermined by site SOPs and consistent with IRB/EC policies and procedures:Potential participant is willing and able to provide written informed consent forstudy participation.

Note: All sites must follow all applicable IRB/EC policies and procedures.

• Assigned female sex at birth, as determined by the site investigator based onparticipant and parent/guardian report and available medical records

• Age less than 18 years of age at entry

Note: Neonates (defined as children who are 28 days of age or younger [≤28 days of age]) may be allowed to enroll after CMC and SMC evaluation of safety and PK data at the interim analysis.

• Weight greater than or equal to 4 kg at entry

• Has confirmed or probable intrathoracic (pulmonary) RR-TB and/or any form ofextrathoracic (extrapulmonary) RR-TB (other than stage 2 or 3 TB meningitis, whichis exclusionary)

• Confirmed intrathoracic (pulmonary) RR-TB, based on chest radiograph and/orsymptoms consistent with TB, and/or any forms of extrathoracic TB, with all ofthe following, as determined by the site investigator based on medical records:

• Microbiological confirmation of M. tuberculosis from any clinical specimenby either culture or molecular methods

• Rifampicin resistance demonstrated by genotypic (molecular) or phenotypicmethods

• Documented clinical decision to treat for RR-TB

Note: In the case of discrepant genotypic and phenotypic test results (i.e., rifampicin-susceptible by one method and rifampicin-resistant by another), this criterion will be considered to have been met if at least one rifampicin-resistant result is available and the participant is assessed as having RR-TB by the non-study care provider when study staff evaluate the participant for eligibility.

• Probable intrathoracic (pulmonary) RR-TB, based on chest radiograph and/or symptomsconsistent with TB, and/or any form of extrathoracic TB, with both of the following,as determined by the site investigator based on medical records:

• Documented exposure to a source case with bacteriologically-confirmedintrathoracic rifampicin-resistant TB

• Documented clinical decision to treat for RR-TB

Note: Full resistance profiles may be obtained after study entry.

• Initiated an appropriate TB OBR treatment regimen as per routine treatment decision,at least two weeks prior to entry, as determined by the site investigator based onmedical records, and is tolerating the regimen well at entry, in the opinion of thesite investigator

Note: see exclusion criterion below for exclusionary TB medications

• Has normal, grade 1, or grade 2 results for all of the following at screening (i.e.,from specimens collected within 28 days prior to entry), based on grading per theDivision of AIDS Table for Grading the Severity of Adult and Pediatric AdverseEvents (DAIDS AE Grading Table; refer to protocol for guidance on severity grading):

• Creatinine

• Platelets

• Absolute neutrophil count

• Hemoglobin

• Estimated glomerular filtration rate (eGFR; bedside Schwartz formula)

Note: Laboratory tests may be repeated during the study screening period (i.e., within 28 days prior to entry), with the latest results used for eligibility determination.

• Has normal or grade 1 results for all of the following at screening (i.e., fromspecimens collected within 28 days prior to entry), based on grading per the DAIDSAE Grading Table (refer to protocol for guidance on severity grading):

• Alanine aminotransferase (ALT)

• Lipase

• Total bilirubin

Note: Laboratory tests may be repeated during the study screening period (i.e., within 28 days prior to entry), with the latest results used for eligibility determination.

• Has a normal QT interval corrected by Fridericia's formula (QTcF) (mean intervalvalue less than 450 milliseconds, on ECG performed in triplicate) at screening

Note: The mean QTcF value obtained from the centralized ECG reading must be used for eligibility determination.

• Has a Karnofsky score greater than or equal to 50% for participants 16 years of ageand older or Lansky play score greater than or equal to 50% for participants lessthan 16 years of age, at screening

• Does not have severe acute malnutrition, defined below, and has no presence ofnutritional edema, based on physical examination, at screening

• Severe acute malnutrition is defined as any of the following:

• For participants 5 years of age and younger: weight-for-height z-scoreless than -3, according to WHO growth standards

• For participants 6 months to 5 years of age: mid-upper arm circumference (MUAC) less than 115 mm

• For participants older than 5 years of age: BMI z-score less than -3,according to WHO growth standards

Note: Children who are stunted may be enrolled.

• HIV status determined based on testing methods meeting the requirements specified inprotocol

• For participants living with HIV, has been taking a stable ARV regimen for at leasttwo consecutive weeks at entry, as determined by the site investigator based onparticipant and parent/guardian report and available medical records

Note: Dose and formulation changes (e.g., for growth) within the two weeks prior to entry are permitted. See below for exclusionary ARVs.

• For participants who have reached menarche or who are engaging in sexual activity (self-reported): not pregnant based on testing performed within 5 days prior toentry during the study screening period (i.e., within 28 days prior to entry)

• For participants who are engaging in sexual activity (self-reported): agrees to useat least one effective, medically accepted birth control method while on study,based on participant and parent/guardian report at entry

• Expected to be available for two weeks of study participation, based on participantand parent/guardian report at entry

Exclusion Criteria:

• Has tuberculosis meningitis Stage 2 or 3, as determined by the site investigatorbased on medical records

• Receipt of any of the following, within 14 days prior to entry, as determined by thesite investigator based on participant/parent/guardian report and available medicalrecords

• Rifamycins

• Any prohibited medication (see protocol for listing)

• For participants living with HIV: ritonavir-boosted protease inhibitors (e.g.,ritonavir-boosted lopinavir, ritonavir-boosted darunavir), atazanavir,nevirapine etravirine, efavirenz, or cobicistat

• Receipt of any investigational agent or device within 28 days prior to entry, asdetermined by the site investigator based on participant/parent/guardian report andavailable medical records

Note: Co-enrollment in COVID-19 vaccine studies and receipt of a COVID-19 vaccine under emergency use authorization (or local equivalent) is allowed, with prior approval from the CMC.

Note: Any co-enrollment must be approved as noted in protocol

• Has any of the following as determined by the site investigator based onparticipant/ parent/guardian report and available medical records

• Clinical evidence of acute hepatitis A, B, C, or chronic hepatitis B or C

• Significant cardiac arrhythmia that requires medication or increases the riskfor Torsade de Pointes

• Known allergy or hypersensitivity to pretomanid or other nitroimidazolecompounds

• Known porphyria

• Currently breastfeeding an infant at entry, as determined by the site investigatorbased on participant/parent/guardian report

• Exposed to pretomanid through breast milk within seven days prior to entry (i.e.,mother receiving pretomanid and breastfeeding a potential participant), asdetermined by the site investigator based on parent/guardian report

• Has any documented or suspected clinically significant medical condition or anyother 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 study objectives