Overview
The purpose of the study is to evaluate the pharmacokinetics (PK), safety, tolerability, and acceptability of a single dose of pretomanid, added to an optimized background tuberculosis treatment regimen (OBR), in children with rifampicin-resistant tuberculosis (RR-TB) with or without human immunodeficiency virus (HIV).
Description
This is a Phase I, multi-site, open-label, non-comparative study of the PK, safety, tolerability, and acceptability of a single-dose of pretomanid added to an OBR in infants, children, and adolescents with RR-TB. The term children is used within the protocol to indicate the total age range from infants through adolescents; enrollment will be limited to children assigned female sex at birth and enrollment of neonates will be deferred until safety and pharmacokinetic data are available in older groups, pending review by the CMC and SMC during the interim analysis. Refer to the study design and the study eligibility criteria and a description of the study recruitment, screening, and enrollment process. Participants are expected to be enrolled at study sites in Brazil, India, South Africa, Tanzania, and Thailand. Up to 72 participants will be enrolled to achieve at least nine evaluable participants in each of four weight groups, for a total of at least 36 enrolled participants.
Participants will receive a single dose of pretomanid on the day of study entry. No additional doses of pretomanid will be administered; participants will continue their OBR. Intensive PK sampling and safety monitoring will be performed on the day of study entry and over the course of the next 48 hours. Participants will then complete a final study visit approximately two weeks after study entry.
Eligibility
Inclusion Criteria:
- If not of legal age or circumstance to provide independent informed consent as determined by site standard operating procedures (SOPs) and consistent with institutional review board/ethics committee (IRB/EC) policies and procedures: Parent/legal guardian is willing and able to provide written informed consent for potential participant's study participation; in addition, when applicable per IRB/EC policies and procedures, potential participant is willing and able to provide written assent for study participation.
- If of legal age or circumstance to provide independent informed consent as determined by site SOPs and consistent with IRB/EC policies and procedures: Potential participant is willing and able to provide written informed consent for study 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 on participant 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 of
extrathoracic (extrapulmonary) RR-TB (other than stage 2 or 3 TB meningitis, which is
exclusionary)
- Confirmed intrathoracic (pulmonary) RR-TB, based on chest radiograph and/or
symptoms consistent with TB, and/or any forms of extrathoracic TB, with all of
the following, as determined by the site investigator based on medical records:
- Microbiological confirmation of M. tuberculosis from any clinical specimen
by either culture or molecular methods
- Rifampicin resistance demonstrated by genotypic (molecular) or phenotypic
methods
- 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 symptoms
consistent 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-confirmed
intrathoracic 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 on
medical records, and is tolerating the regimen well at entry, in the opinion of the
site 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 the
Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events
(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., from
specimens collected within 28 days prior to entry), based on grading per the DAIDS AE
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 interval value
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 age
and older or Lansky play score greater than or equal to 50% for participants less than
16 years of age, at screening
- Does not have severe acute malnutrition, defined below, and has no presence of
nutritional 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-score less
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 in
protocol
- For participants living with HIV, has been taking a stable ARV regimen for at least
two consecutive weeks at entry, as determined by the site investigator based on
participant 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 to entry
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 use at
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 participant
and parent/guardian report at entry
Exclusion Criteria:
- Has tuberculosis meningitis Stage 2 or 3, as determined by the site investigator based
on medical records
- Receipt of any of the following, within 14 days prior to entry, as determined by the
site investigator based on participant/parent/guardian report and available medical
records
- 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, as
determined by the site investigator based on participant/parent/guardian report and
available 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 on participant/
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 risk for
Torsade de Pointes
- Known allergy or hypersensitivity to pretomanid or other nitroimidazole compounds
- Known porphyria
- Currently breastfeeding an infant at entry, as determined by the site investigator
based 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), as determined
by the site investigator based on parent/guardian report
- Has any documented or suspected clinically significant medical condition or any other
condition that, in the opinion of the site investigator, would make participation in
the study unsafe, complicate interpretation of study outcome data, or otherwise
interfere with achieving study objectives